Histone demethylase inhibitors

ABSTRACT

The present invention relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted pyrrolopyridine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/842,700, filed Dec. 14, 2017, which is a continuation of U.S. patentapplication Ser. No. 15/652,174, filed Jul. 17, 2017 (now U.S. Pat. No.9,873,697, issued Jan. 23, 2018), which is a divisional of U.S. patentapplication Ser. No. 14/774,329, filed Sep. 10, 2015 (now U.S. Pat. No.9,738,637, issued Aug. 22, 2017), which is a National Stage Applicationof PCT/US2014/023273, filed Mar. 11, 2014, which claims the prioritybenefit of U.S. Provisional Application 61/778,193, filed Mar. 12, 2013,the contents of which are hereby incorporated by reference in theirentireties.

BACKGROUND

A need exists in the art for an effective treatment of cancer andneoplastic disease.

BRIEF SUMMARY OF THE INVENTION

Provided herein are substituted pyrrolopyridine derivative compounds andpharmaceutical compositions comprising said compounds. The subjectcompounds and compositions are useful for inhibition histonedemethylase. Furthermore, the subject compounds and compositions areuseful for the treatment of cancer, such as prostate cancer, breastcancer, bladder cancer, lung cancer and/or melanoma and the like. Thesubstituted pyrrolopyridine derivative compounds described herein arebased upon a disubstituted pyrrolo[3,2-b]pyridine ring system bearing atthe 7-position a carboxylic acid or bioisostere thereof, and a secondsubstituent at the 2-position. The 2-position substituent, in variousembodiments, is selected from a wide variety of groups, such as, but notlimited to, alkyl, aryl, carbocyclyl, and the like.

One embodiment provides a compound having the structure of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein,

Y is —CO₂R¹, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl, wherein

-   -   R¹ is hydrogen or alkyl;

G is X—R² or X¹-alkyl, wherein

-   -   X is a bond, alkylene, alkylene-O—, —C(O)—, —C(O)—NH—, —NH—,        —NH—C(O)—, —O—, —S—, or —SO₂—;    -   R² is selected from carbocyclyl, heterocyclyl, aryl, or        heteroaryl;    -   X¹ is a bond, —C(O)—, —C(O)—NH—, —NH—, —NH—C(O)—, —O—, —S—, or        —SO₂—; and

R³ is hydrogen, halogen, or alkyl.

Another embodiment provides the compound of Formula (I) represented bythe structure of Formula (II),

or a pharmaceutically acceptable salt thereof, wherein,

R¹ is hydrogen or alkyl;

G is X—R² or X¹-alkyl, wherein

-   -   X is a bond, alkylene, alkylene-O—, —C(O)—, —C(O)—NH—, —NH—,        —NH—C(O)—, —O—, —S—, or —SO₂—;    -   R² is selected from carbocyclyl, heterocyclyl, aryl, or        heteroaryl;    -   X¹ is a bond, —C(O)—, —C(O)—NH—, —NH—, —NH—C(O)—, —O—, —S—, or        —SO₂—; and

R³ is hydrogen, halogen or alkyl.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I) or apharmaceutically acceptable salt thereof.

One embodiment provides a method for treating cancer in subjectcomprising administering a composition comprising a compound of Formula(I) or a pharmaceutically acceptable salt thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

DEFINITIONS

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₅ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅alkyl). In other embodiments, the alkyl group is selected from methyl,ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₅ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —Re-aryl where R^(c) is analkylene chain as defined above, for example, methylene, ethylene, andthe like. The alkylene chain part of the aralkyl radical is optionallysubstituted as described above for an alkylene chain. The aryl part ofthe aralkyl radical is optionally substituted as described above for anaryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl may be saturated, (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds.) A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclo-octenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo-[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical may be optionally substituted asdefined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. The heteroatoms in theheterocyclyl radical may be optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl may be attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxothiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)OC(O)R^(a), —R^(b)OC(O)OR^(a), —R^(b)OC(O)N(R^(a))₂,—R^(b)N(R^(a))₂, —R^(b)C(O)R^(a), —R^(b)C(O)OR^(a), —R^(b)C(O)N(R^(a))₂,—R^(b)OR_(c)C(O)N(R^(a))₂, —R^(b)N(R^(a))C(O)OR^(a),—R^(b)N(R^(a))C(O)R^(a), —R^(b)N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R is an alkylene chain as defined above. Ifthe heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclylis optionally attached to the alkyl radical at the nitrogen atom. Thealkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, pheno-thiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]-pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]-pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)OC(O)R^(a), —R^(b)OC(O)OR^(a),—R^(b)OC(O)N(R^(a))₂, —R^(b)N(R^(a))₂, —R^(b)C(O)R^(a),—R^(b)C(O)OR^(a), —R^(b)C(O)N(R^(a))₂, —R^(b)OR_(c)C(O)N(R^(a))₂,—R^(b)N(R^(a))C(O)OR^(a), —R^(b)N(R^(a))C(O)R^(a),—R^(b)N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

The compounds disclosed herein may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans). Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the substitutedpyrrolopyridine derivative compounds described herein is intended toencompass any and all pharmaceutically suitable salt forms. Preferredpharmaceutically acceptable salts of the compounds described herein arepharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitro-benzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997), which is hereby incorporated byreference in its entirety). Acid addition salts of basic compounds maybe prepared by contacting the free base forms with a sufficient amountof the desired acid to produce the salt according to methods andtechniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds, and the like.

Substituted Pyrrolopyridine Derivative Compounds

Substituted pyrrolopyridine derivative compounds are described hereinthat inhibit a histone demethylase enzyme. These compounds, andcompositions comprising these compounds, are useful for the treatment ofcancer and neoplastic disease. The compounds described herein may,therefore, be useful for treating prostate cancer, breast cancer,bladder cancer, lung cancer and/or melanoma and the like.

One embodiment provides a compound having the structure of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein,

Y is —CO₂R¹, —C(O)N(H)CN, —C(O)N(H)OH or tetrazolyl;

-   -   R¹ is hydrogen or alkyl;

G is X—R² or X¹-alkyl, wherein

-   -   X is a bond, alkylene, alkylene-O—, —C(O)—, —C(O)—NH—, —NH—,        —NH—C(O)—, —O—, —S—, or —SO₂—;    -   R² is selected from carbocyclyl, heterocyclyl, aryl, or        heteroaryl;    -   X¹ is a bond, —C(O)—, —C(O)—NH—, —NH—, —NH—C(O)—, —O—, —S—, or        —SO₂—; and

R³ is hydrogen, halogen or alkyl.

Another embodiment provides the compound having the structure of Formula(I), wherein Y is —CO₂R¹ and R¹ is hydrogen. Another embodiment providesthe compound having the structure of Formula (I), wherein Y is —CO₂R¹and R¹ is alkyl. Another embodiment provides the compound having thestructure of Formula (I), wherein Y is —C(O)N(H)CN. Another embodimentprovides the compound having the structure of Formula (I), wherein Y is—C(O)N(H)OH. Another embodiment provides the compound having thestructure of Formula (I), wherein Y is tetrazolyl.

Another embodiment provides the compound having the structure of Formula(I), wherein R³ is hydrogen.

Another embodiment provides the compound having the structure of Formula(I), wherein G is X—R². Another embodiment provides the compound havingthe structure of Formula (I), wherein X is a bond and R² is aryl.Another embodiment provides the compound having the structure of Formula(I), wherein X is alkylene and R² is aryl. Another embodiment providesthe compound having the structure of Formula (I), wherein alkylene issubstituted with —OH, alkoxy, alkylamino, or dialkylamino. Anotherembodiment provides the compound having the structure of Formula (I),wherein X is a C₁-C₃ alkylene and R² is aryl. Another embodimentprovides the compound having the structure of Formula (I), wherein X isa bond and R² is carbocyclyl. Another embodiment provides the compoundhaving the structure of Formula (I), wherein R² is C₃-C₇ carbocyclyl.Another embodiment provides the compound having the structure of Formula(I), wherein the carbocyclyl is a 1-hydroxy carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (I),wherein X is a bond and R² is heteroaryl. Another embodiment providesthe compound having the structure of Formula (I), wherein X is a bondand R² is heterocyclyl. Another embodiment provides the compound havingthe structure of Formula (I), wherein X is alkylene and R² iscarbocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein alkylene is substituted with —OH,alkoxy, alkylamino, or dialkylamino. Another embodiment provides thecompound having the structure of Formula (I), wherein R² is C₃-C₇carbocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein X is C₁-C₃ alkylene and R² iscarbocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein R² is C₃-C₇ carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (I),wherein X is alkylene and R² is heteroaryl. Another embodiment providesthe compound having the structure of Formula (I), wherein alkylene issubstituted with —OH, alkoxy, alkylamino, or dialkylamino. Anotherembodiment provides the compound having the structure of Formula (I),wherein X is C₁-C₃ alkylene and R² is heteroaryl. Another embodimentprovides the compound having the structure of Formula (I), wherein X isalkylene and R² is heterocyclyl. Another embodiment provides thecompound having the structure of Formula (I), wherein alkylene issubstituted with —OH, alkoxy, alkylamino, or dialkylamino. Anotherembodiment provides the compound having the structure of Formula (I),wherein X is C₁-C₃ alkylene and R² is heterocyclyl. Another embodimentprovides the compound having the structure of Formula (I), wherein X is—C(O)— and R² is aryl. Another embodiment provides the compound havingthe structure of Formula (I), wherein X is —C(O)— and R² is heteroaryl.Another embodiment provides the compound having the structure of Formula(I), wherein X is —C(O)— and R² is carbocyclyl. Another embodimentprovides the compound having the structure of Formula (I), wherein R² isC₃-C₇ carbocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein X is —C(O)— and R² is heterocyclyl.Another embodiment provides the compound having the structure of Formula(I), wherein X is —C(O)—NH— and R² is aryl. Another embodiment providesthe compound having the structure of Formula (I), wherein X is —C(O)—NH—and R² is heteroaryl. Another embodiment provides the compound havingthe structure of Formula (I), wherein X is —C(O)—NH— and R² iscarbocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein R² is C₃-C₇ carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (I),wherein X is —C(O)—NH— and R² is heterocyclyl. Another embodimentprovides the compound having the structure of Formula (I), wherein X is—NH— and R² is aryl. Another embodiment provides the compound having thestructure of Formula (I), wherein X is —NH— and R² is heteroaryl.Another embodiment provides the compound having the structure of Formula(I), wherein X is —NH— and R² is carbocyclyl. Another embodimentprovides the compound having the structure of Formula (I), wherein R² isC₃-C₇ carbocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein X is —NH— and R² is heterocyclyl.Another embodiment provides the compound having the structure of Formula(I), wherein X is —NH—C(O)— and R² is aryl. Another embodiment providesthe compound having the structure of Formula (I), wherein X is —NH—C(O)—and R² is heteroaryl. Another embodiment provides the compound havingthe structure of Formula (I), wherein X is —NH—C(O)— and R² iscarbocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein R² is C₃-C₇ carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (I),wherein X is —NH—C(O)— and R² is heterocyclyl. Another embodimentprovides the compound having the structure of Formula (I), wherein X is—O— and R² is aryl. Another embodiment provides the compound having thestructure of Formula (I), wherein X is —O— and R² is heteroaryl. Anotherembodiment provides the compound having the structure of Formula (I),wherein X is —O— and R² is carbocyclyl. Another embodiment provides thecompound having the structure of Formula (I), wherein R² is C₃-C₇carbocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein X is —O— and R² is heterocyclyl.Another embodiment provides the compound having the structure of Formula(I), wherein X is —S— and R² is aryl. Another embodiment provides thecompound having the structure of Formula (I), wherein X is —S— and R² isheteroaryl. Another embodiment provides the compound having thestructure of Formula (I), wherein X is —S— and R² is carbocyclyl.Another embodiment provides the compound having the structure of Formula(I), wherein R² is C₃-C₇ carbocyclyl. Another embodiment provides thecompound having the structure of Formula (I), wherein X is —S— and R² isheterocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein X is —SO₂— and R² is aryl. Anotherembodiment provides the compound having the structure of Formula (I),wherein X is —SO₂— and R² is heteroaryl. Another embodiment provides thecompound having the structure of Formula (I), wherein X is —SO₂— and R²is carbocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein R² is C₃-C₇ carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (I),wherein X is —SO₂— and R² is heterocyclyl.

Another embodiment provides the compound having the structure of Formula(I), wherein G is X¹-alkyl. Another embodiment provides the compoundhaving the structure of Formula (I), wherein X¹ is a bond. Anotherembodiment provides the compound having the structure of Formula (I),wherein the alkyl is a C₁-C₄ alkyl. Another embodiment provides thecompound having the structure of Formula (I), wherein the alkyl is a1-hydroxyalkyl. Another embodiment provides the compound having thestructure of Formula (I), wherein the alkyl is a C₂-C₄ 1-hydroxyalkyl.Another embodiment provides the compound having the structure of Formula(I), wherein X¹ is —C(O)—. Another embodiment provides the compoundhaving the structure of Formula (I), wherein the alkyl is a C₁-C₄ alkyl.Another embodiment provides the compound having the structure of Formula(I), wherein X¹ is —C(O)—NH—. Another embodiment provides the compoundhaving the structure of Formula (I), wherein the alkyl is a C₁-C₄ alkyl.Another embodiment provides the compound having the structure of Formula(I), wherein X¹ is —NH—. Another embodiment provides the compound havingthe structure of Formula (I), wherein the alkyl is a C₁-C₄ alkyl.Another embodiment provides the compound having the structure of Formula(I), wherein X¹ is —NH—C(O)—. Another embodiment provides the compoundhaving the structure of Formula (I), wherein the alkyl is a C₁-C₄ alkyl.Another embodiment provides the compound having the structure of Formula(I), wherein X¹ is —O—. Another embodiment provides the compound havingthe structure of Formula (I), wherein the alkyl is a C₁-C₄ alkyl.Another embodiment provides the compound having the structure of Formula(I), wherein X¹ is —S—. Another embodiment provides the compound havingthe structure of Formula (I), wherein the alkyl is a C₁-C₄ alkyl.Another embodiment provides the compound having the structure of Formula(I), wherein X¹ is —SO₂—. Another embodiment provides the compoundhaving the structure of Formula (I), wherein the alkyl is a C₁-C₄ alkyl.Another embodiment provides the compound having the structure of Formula(I), wherein X is alkylene-O—. Another embodiment provides the compoundhaving the structure of Formula (I), wherein X is alkylene-O—, and R² isaryl. Another embodiment provides the compound having the structure ofFormula (I), wherein X is alkylene-O—, and R² is heteroaryl. Anotherembodiment provides the compound having the structure of Formula (I),wherein X is alkylene-O—, and R² is carbocyclyl. Another embodimentprovides the compound having the structure of Formula (I), wherein R² isC₃-C₇ carbocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein X is alkylene-O—, and R² isheterocyclyl. Another embodiment provides the compound having thestructure of Formula (I), wherein the alkylene is a C₁-C₃ alkylene.

Another embodiment provides the compound of Formula (I) represented bythe structure of Formula (II),

or a pharmaceutically acceptable salt thereof, wherein

R¹ is hydrogen or alkyl;

G is X—R² or X¹-alkyl, wherein

-   -   X is a bond, alkylene, alkylene-O—, —C(O)—, —C(O)—NH—, —NH—,        —NH—C(O)—, —O—, —S—, or —SO₂—;    -   R² is selected from carbocyclyl, heterocyclyl, aryl, or        heteroaryl;    -   X¹ is a bond, —C(O)—, —C(O)—NH—, —NH—, —NH—C(O)—, —O—, —S—, or        —SO₂—; and

R³ is hydrogen, halogen or alkyl.

Another embodiment provides the compound having the structure of Formula(II), wherein R¹ is hydrogen. Another embodiment provides the compoundhaving the structure of Formula (II), wherein R¹ is alkyl. Anotherembodiment provides the compound having the structure of Formula (II),wherein G is X—R². Another embodiment provides the compound having thestructure of Formula (II), wherein X is a bond and R² is aryl. Anotherembodiment provides the compound having the structure of Formula (II),wherein X is alkylene and R² is aryl. Another embodiment provides thecompound having the structure of Formula (II), wherein alkylene issubstituted with —OH, alkoxy, alkylamino, or dialkylamino. Anotherembodiment provides the compound having the structure of Formula (II),wherein X is a C₁-C₃ alkylene and R² is aryl. Another embodimentprovides the compound having the structure of Formula (II), wherein X isa bond and R² is carbocyclyl. Another embodiment provides the compoundhaving the structure of Formula (II), wherein R² is C₃-C₇ carbocyclyl.Another embodiment provides the compound having the structure of Formula(II), wherein the carbocyclyl is a 1-hydroxy carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (II),wherein X is a bond and R² is heteroaryl. Another embodiment providesthe compound having the structure of Formula (II), wherein X is a bondand R² is heterocyclyl. Another embodiment provides the compound havingthe structure of Formula (II), wherein X is alkylene and R² iscarbocyclyl. Another embodiment provides the compound having thestructure of Formula (II), wherein alkylene is substituted with —OH,alkoxy, alkylamino, or dialkylamino. Another embodiment provides thecompound having the structure of Formula (II), wherein R² is C₃-C₇carbocyclyl. Another embodiment provides the compound having thestructure of Formula (II), wherein X is C₁-C₃ alkylene and R² iscarbocyclyl. Another embodiment provides the compound having thestructure of Formula (II), wherein R² is C₃-C₇ carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (II),wherein X is alkylene and R² is heteroaryl. Another embodiment providesthe compound having the structure of Formula (II), wherein alkylene issubstituted with —OH, alkoxy, alkylamino, or dialkylamino. Anotherembodiment provides the compound having the structure of Formula (II),wherein X is C₁-C₃ alkylene and R² is heteroaryl. Another embodimentprovides the compound having the structure of Formula (II), wherein X isalkylene and R² is heterocyclyl. Another embodiment provides thecompound having the structure of Formula (II), wherein alkylene issubstituted with —OH, alkoxy, alkylamino, or dialkylamino. Anotherembodiment provides the compound having the structure of Formula (II),wherein X is C₁-C₃ alkylene and R² is heterocyclyl. Another embodimentprovides the compound having the structure of Formula (II), wherein X is—C(O)— and R² is aryl. Another embodiment provides the compound havingthe structure of Formula (II), wherein X is —C(O)— and R² is heteroaryl.Another embodiment provides the compound having the structure of Formula(II), wherein X is —C(O)— and R² is carbocyclyl. Another embodimentprovides the compound having the structure of Formula (II), wherein R²is C₃-C₇ carbocyclyl. Another embodiment provides the compound havingthe structure of Formula (II), wherein X is —C(O)— and R² isheterocyclyl. Another embodiment provides the compound having thestructure of Formula (II), wherein X is —C(O)—NH— and R² is aryl.Another embodiment provides the compound having the structure of Formula(II), wherein X is —C(O)—NH— and R² is heteroaryl. Another embodimentprovides the compound having the structure of Formula (II), wherein X is—C(O)—NH— and R² is carbocyclyl. Another embodiment provides thecompound having the structure of Formula (II), wherein R² is C₃-C₇carbocyclyl. Another embodiment provides the compound having thestructure of Formula (II), wherein X is —C(O)—NH— and R² isheterocyclyl. Another embodiment provides the compound having thestructure of Formula (II), wherein X is —NH— and R² is aryl. Anotherembodiment provides the compound having the structure of Formula (II),wherein X is —NH— and R² is heteroaryl. Another embodiment provides thecompound having the structure of Formula (II), wherein X is —NH— and R²is carbocyclyl. Another embodiment provides the compound having thestructure of Formula (II), wherein R² is C₃-C₇ carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (II),wherein X is —NH— and R² is heterocyclyl. Another embodiment providesthe compound having the structure of Formula (II), wherein X is—NH—C(O)— and R² is aryl. Another embodiment provides the compoundhaving the structure of Formula (II), wherein X is —NH—C(O)— and R² isheteroaryl. Another embodiment provides the compound having thestructure of Formula (II), wherein X is —NH—C(O)— and R² is carbocyclyl.Another embodiment provides the compound having the structure of Formula(II), wherein R² is C₃-C₇ carbocyclyl. Another embodiment provides thecompound having the structure of Formula (II), wherein X is —NH—C(O)—and R² is heterocyclyl. Another embodiment provides the compound havingthe structure of Formula (II), wherein X is —O— and R² is aryl. Anotherembodiment provides the compound having the structure of Formula (II),wherein X is —O— and R² is heteroaryl. Another embodiment provides thecompound having the structure of Formula (II), wherein X is —O— and R²is carbocyclyl. Another embodiment provides the compound having thestructure of Formula (II), wherein R² is C₃-C₇ carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (II),wherein X is —O— and R² is heterocyclyl. Another embodiment provides thecompound having the structure of Formula (II), wherein X is —S— and R²is aryl. Another embodiment provides the compound having the structureof Formula (II), wherein X is —S— and R² is heteroaryl. Anotherembodiment provides the compound having the structure of Formula (II),wherein X is —S— and R² is carbocyclyl. Another embodiment provides thecompound having the structure of Formula (II), wherein R² is C₃-C₇carbocyclyl. Another embodiment provides the compound having thestructure of Formula (II), wherein X is —S— and R² is heterocyclyl.Another embodiment provides the compound having the structure of Formula(II), wherein X is —SO₂— and R² is aryl. Another embodiment provides thecompound having the structure of Formula (II), wherein X is —SO₂— and R²is heteroaryl. Another embodiment provides the compound having thestructure of Formula (II), wherein X is —SO₂— and R² is carbocyclyl.Another embodiment provides the compound having the structure of Formula(II), wherein R² is C₃-C₇ carbocyclyl. Another embodiment provides thecompound having the structure of Formula (II), wherein X is —SO₂— and R²is heterocyclyl.

Another embodiment provides the compound having the structure of Formula(II), wherein G is X¹-alkyl. Another embodiment provides the compoundhaving the structure of Formula (II), wherein X¹ is a bond. Anotherembodiment provides the compound having the structure of Formula (II),wherein the alkyl is a C₁-C₄ alkyl. Another embodiment provides thecompound having the structure of Formula (II), wherein the alkyl is a1-hydroxyalkyl. Another embodiment provides the compound having thestructure of Formula (II), wherein the alkyl is a C₂-C₄ 1-hydroxyalkyl.Another embodiment provides the compound having the structure of Formula(II), wherein X¹ is —C(O)—. Another embodiment provides the compoundhaving the structure of Formula (II), wherein the alkyl is a C₁-C₄alkyl. Another embodiment provides the compound having the structure ofFormula (II), wherein X¹ is —C(O)—NH—. Another embodiment provides thecompound having the structure of Formula (II), wherein the alkyl is aC₁-C₄ alkyl. Another embodiment provides the compound having thestructure of Formula (II), wherein X¹ is —NH—. Another embodimentprovides the compound having the structure of Formula (II), wherein thealkyl is a C₁-C₄ alkyl. Another embodiment provides the compound havingthe structure of Formula (II), wherein X¹ is —NH—C(O)—. Anotherembodiment provides the compound having the structure of Formula (II),wherein the alkyl is a C₁-C₄ alkyl. Another embodiment provides thecompound having the structure of Formula (II), wherein X¹ is —O—.Another embodiment provides the compound having the structure of Formula(II), wherein the alkyl is a C₁-C₄ alkyl. Another embodiment providesthe compound having the structure of Formula (II), wherein X¹ is —S—.Another embodiment provides the compound having the structure of Formula(II), wherein the alkyl is a C₁-C₄ alkyl. Another embodiment providesthe compound having the structure of Formula (II), wherein X¹ is —SO₂—.Another embodiment provides the compound having the structure of Formula(II), wherein the alkyl is a C₁-C₄ alkyl. Another embodiment providesthe compound having the structure of Formula (II), wherein X isalkylene-O—. Another embodiment provides the compound having thestructure of Formula (II), wherein X is alkylene-O—, and R² is aryl.Another embodiment provides the compound having the structure of Formula(II), wherein X is alkylene-O—, and R² is heteroaryl. Another embodimentprovides the compound having the structure of Formula (II), wherein X isalkylene-O—, and R² is carbocyclyl. Another embodiment provides thecompound having the structure of Formula (II), wherein R² is C₃-C₇carbocyclyl. Another embodiment provides the compound having thestructure of Formula (II), wherein X is alkylene-O—, and R² isheterocyclyl. Another embodiment provides the compound having thestructure of Formula (II), wherein the alkylene is a C₁-C₃ alkylene.

One embodiment provides a compound having the structure of Formula (Ia),

or a pharmaceutically acceptable salt thereof, wherein,

Y is —CO₂R¹, —C(O)NH—(C₁-C₃)alkyl, —C(O)N(H)CN, —C(O)N(H)OH ortetrazolyl;

-   -   R¹ is hydrogen, alkyl, heterocyclylalkyl, or carbocyclylalkyl;

G is X—R² or X¹-alkyl, wherein

-   -   X is a bond, alkylene, alkylene-O—, —C(O)—, —C(O)—NH—, —NH—,        —NH—C(O)—, —O—, —S—, or —SO₂—;    -   R² is selected from carbocyclyl, heterocyclyl, aryl, or        heteroaryl;    -   X¹ is a bond, —C(O)—, —C(O)—NH—, —NH—, —NH—C(O)—, —O—, —S—, or        —SO₂—; and

R³ is hydrogen, halogen or alkyl.

Another embodiment provides the compound having the structure of Formula(Ia), wherein Y is —CO₂R¹ and R¹ is hydrogen. Another embodimentprovides the compound having the structure of Formula (Ia), wherein Y is—CO₂R¹ and R¹ is alkyl. Another embodiment provides the compound havingthe structure of Formula (Ia), wherein Y is —CO₂R¹ and R¹ isheterocyclylalkyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein Y is —CO₂R¹ and R¹ iscarbocyclylalkyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein Y is —C(O)NH—(C₁-C₃)alkyl. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein Y is —C(O)N(H)CN. Another embodiment provides the compoundhaving the structure of Formula (Ia), wherein Y is —C(O)N(H)OH. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein Y is tetrazolyl.

Another embodiment provides the compound having the structure of Formula(Ia), wherein R³ is hydrogen.

Another embodiment provides the compound having the structure of Formula(Ia), wherein G is X—R². Another embodiment provides the compound havingthe structure of Formula (Ia), wherein X is a bond and R² is aryl.Another embodiment provides the compound having the structure of Formula(Ia), wherein X is alkylene and R² is aryl. Another embodiment providesthe compound having the structure of Formula (Ia), wherein alkylene issubstituted with —OH, alkoxy, alkylamino, or dialkylamino. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein X is a C₁-C₃ alkylene and R² is aryl. Another embodimentprovides the compound having the structure of Formula (Ia), wherein X isa bond and R² is carbocyclyl. Another embodiment provides the compoundhaving the structure of Formula (Ia), wherein R² is C₃-C₇ carbocyclyl.Another embodiment provides the compound having the structure of Formula(Ia), wherein the carbocyclyl is a 1-hydroxy carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein X is a bond and R² is heteroaryl. Another embodiment providesthe compound having the structure of Formula (Ia), wherein X is a bondand R² is heterocyclyl. Another embodiment provides the compound havingthe structure of Formula (Ia), wherein X is alkylene and R² iscarbocyclyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein alkylene is substituted with —OH,alkoxy, alkylamino, or dialkylamino. Another embodiment provides thecompound having the structure of Formula (Ia), wherein R² is C₃-C₇carbocyclyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein X is C₁-C₃ alkylene and R² iscarbocyclyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein R² is C₃-C₇ carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein X is alkylene and R² is heteroaryl. Another embodiment providesthe compound having the structure of Formula (Ia), wherein alkylene issubstituted with —OH, alkoxy, alkylamino, or dialkylamino. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein X is C₁-C₃ alkylene and R² is heteroaryl. Another embodimentprovides the compound having the structure of Formula (Ia), wherein X isalkylene and R² is heterocyclyl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein alkylene issubstituted with —OH, alkoxy, alkylamino, or dialkylamino. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein X is C₁-C₃ alkylene and R² is heterocyclyl. Another embodimentprovides the compound having the structure of Formula (Ia), wherein X is—C(O)— and R² is aryl. Another embodiment provides the compound havingthe structure of Formula (Ia), wherein X is —C(O)— and R² is heteroaryl.Another embodiment provides the compound having the structure of Formula(Ia), wherein X is —C(O)— and R² is carbocyclyl. Another embodimentprovides the compound having the structure of Formula (Ia), wherein R²is C₃-C₇ carbocyclyl. Another embodiment provides the compound havingthe structure of Formula (Ia), wherein X is —C(O)— and R² isheterocyclyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein X is —C(O)—NH— and R² is aryl.Another embodiment provides the compound having the structure of Formula(Ia), wherein X is —C(O)—NH— and R² is heteroaryl. Another embodimentprovides the compound having the structure of Formula (Ia), wherein X is—C(O)—NH— and R² is carbocyclyl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein R² is C₃-C₇carbocyclyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein X is —C(O)—NH— and R² isheterocyclyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein X is —NH— and R² is aryl. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein X is —NH— and R² is heteroaryl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein X is —NH— and R²is carbocyclyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein R² is C₃-C₇ carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein X is —NH— and R² is heterocyclyl. Another embodiment providesthe compound having the structure of Formula (Ia), wherein X is—NH—C(O)— and R² is aryl. Another embodiment provides the compoundhaving the structure of Formula (Ia), wherein X is —NH—C(O)— and R² isheteroaryl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein X is —NH—C(O)— and R² is carbocyclyl.Another embodiment provides the compound having the structure of Formula(Ia), wherein R² is C₃-C₇ carbocyclyl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein X is —NH—C(O)—and R² is heterocyclyl. Another embodiment provides the compound havingthe structure of Formula (Ia), wherein X is —O— and R² is aryl. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein X is —O— and R² is heteroaryl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein X is —O— and R²is carbocyclyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein R² is C₃-C₇ carbocyclyl. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein X is —O— and R² is heterocyclyl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein X is —S— and R²is aryl. Another embodiment provides the compound having the structureof Formula (Ia), wherein X is —S— and R² is heteroaryl. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein X is —S— and R² is carbocyclyl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein R² is C₃-C₇carbocyclyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein X is —S— and R² is heterocyclyl.Another embodiment provides the compound having the structure of Formula(Ia), wherein X is —SO₂— and R² is aryl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein X is —SO₂— and R²is heteroaryl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein X is —SO₂— and R² is carbocyclyl.Another embodiment provides the compound having the structure of Formula(Ia), wherein R² is C₃-C₇ carbocyclyl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein X is —SO₂— and R²is heterocyclyl.

Another embodiment provides the compound having the structure of Formula(Ia), wherein G is X¹-alkyl. Another embodiment provides the compoundhaving the structure of Formula (Ia), wherein X¹ is a bond. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein the alkyl is a C₁-C₄ alkyl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein the alkyl is a1-hydroxyalkyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein the alkyl is a C₂-C₄ 1-hydroxyalkyl.Another embodiment provides the compound having the structure of Formula(Ia), wherein X¹ is —C(O)—. Another embodiment provides the compoundhaving the structure of Formula (Ia), wherein the alkyl is a C₁-C₄alkyl. Another embodiment provides the compound having the structure ofFormula (Ia), wherein X¹ is —C(O)—NH—. Another embodiment provides thecompound having the structure of Formula (Ia), wherein the alkyl is aC₁-C₄ alkyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein X¹ is —NH—. Another embodimentprovides the compound having the structure of Formula (Ia), wherein thealkyl is a C₁-C₄ alkyl. Another embodiment provides the compound havingthe structure of Formula (Ia), wherein X¹ is —NH—C(O)—. Anotherembodiment provides the compound having the structure of Formula (Ia),wherein the alkyl is a C₁-C₄ alkyl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein X¹ is —O—.Another embodiment provides the compound having the structure of Formula(Ia), wherein the alkyl is a C₁-C₄ alkyl. Another embodiment providesthe compound having the structure of Formula (Ia), wherein X¹ is —S—.Another embodiment provides the compound having the structure of Formula(Ia), wherein the alkyl is a C₁-C₄ alkyl. Another embodiment providesthe compound having the structure of Formula (Ia), wherein X¹ is —SO₂—.Another embodiment provides the compound having the structure of Formula(Ia), wherein the alkyl is a C₁-C₄ alkyl. Another embodiment providesthe compound having the structure of Formula (Ia), wherein X isalkylene-O—. Another embodiment provides the compound having thestructure of Formula (Ia), wherein X is alkylene-O—, and R² is aryl.Another embodiment provides the compound having the structure of Formula(Ia), wherein X is alkylene-O—, and R² is heteroaryl. Another embodimentprovides the compound having the structure of Formula (Ia), wherein X isalkylene-O—, and R² is carbocyclyl. Another embodiment provides thecompound having the structure of Formula (Ia), wherein R² is C₃-C₇carbocyclyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein X is alkylene-O—, and R² isheterocyclyl. Another embodiment provides the compound having thestructure of Formula (Ia), wherein the alkylene is a C₁-C₃ alkylene.

In some embodiments, the compound of Formula (I), (Ia), or (II) asdisclosed herein has the structure provided in Table 1.

TABLE 1 Chemical Synthesis Example Structure Name 1

3-chloro-1H-pyrrolo[3,2-b] pyridine-7-carboxylic acid 2

2-phenyl-1H-pyrrolo[3,2-b] pyridine-7-carboxylic acid 3

2-(2-methylphenyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 6

methyl 2-benzyl-1H-pyrrolo- [3,2-b]pyridine-7-carboxylic acid 7

2-benzyl-1H-pyrrolo[3,2-b] pyridine-7-carboxylic acid 8

2-propyl-1H-pyrrolo[3,2-b] pyridine-7-carboxylic acid 10

2-(hydroxymethyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 11

methyl 2-cyclopropyl-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 12

2-cyclopropyl-1H-pyrrolo- [3,2-b]pyridine-7-carboxylic acid 5

2-(2-hydroxypropan-2-yl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 4

methyl 2-(2-hydroxypropan-2-yl)- 1H-pyrrolo[3,2-b]pyridine-7-carboxylate 13

methyl 2-(1-hydroxycyclohexyl)- 1H-pyrrolo[3,2-b]pyridine- 7-carboxylate14

2-(1-hydroxycyclohexyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 15

methyl 2-(4-methoxy-2- methylphenyl)-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 17

methyl 2-(1-hydroxyethyl)-1H- pyrrolo[3,2-b]pyridine- 7-carboxylate 18

2-(1-hydroxyethyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 16

2-(4-methoxy-2-methylphenyl)- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 20

2-[hydroxy(phenyl)methyl]-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid22

2-[hydroxy-(3-methyl- phenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 24

2-[hydroxy-(3- methoxyphenyl)methyl]-1H- pyrrolo[3,2-b]pyridine-7-carboxylic acid 21

methyl 2-[hydroxy-(3- methylphenyl)methyl]-1H- pyrrolo[3,2-b]pyridine-7-carboxylate 20

methyl 2- [hydroxy(phenyl)methyl]-1H- pyrrolo[3,2-b]pyridine-7-carboxylate 9

methyl 2-(hydroxymethyl)-1H- pyrrolo[3,2-b]pyridine- 7-carboxylate 23

methyl 2-[hydroxy-(3- methoxyphenyl)methyl]-1H- pyrrolo[3,2-b]pyridine-7-carboxylate 25

methyl 2-(1-hydroxypropyl)-1H- pyrrolo[3,2-b]pyridine- 7-carboxylate 27

2-(1-hydroxycyclopentyl)-1H- pyrrolo[3,2-b]pyridine- 7-carboxylic acid29

2-cyclopentyl-1H-pyrrolo[3,2- b]pyridine-7-carboxylic acid 28

methyl 2-cyclopentyl-1H- pyrrolo[3,2-b]pyridine- 7-carboxylate 26

2-(1-hydroxypropyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 30

2-(1-hydroxy-2-methylpropyl)- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 31

methyl 2-(1-hydroxy-2- methylpropyl)-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 33

2-[cyclopropyl(hydroxy)methyl]- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 32

methyl 2-[cyclopropyl- (hydroxy)methyl]-1H- pyrrolo[3,2-b]pyridine-7-carboxylate 34

2-[(3-methoxyphenyl)methyl]- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 35

methyl 2-[(3-methyl- phenyl)methyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 37

methyl 2-(2-cyclopropyl-1- hydroxyethyl)-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 36

2-[(3-methylphenyl)methyl]-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid38

2-(2-cyclopropyl-1- hydroxyethyl)-1H-pyrrolo-[3,2-b]pyridine-7-carboxylic acid 39

2-(phenoxymethyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 41

2-(methoxymethyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 40

methyl 2-(methoxymethyl)-1H- pyrrolo[3,2-b]pyridine- 7-carboxylate 43

2-[hydroxy(oxan-4-yl)methyl]- 1H-pyrrolo[3,2-b]pyridine- 7-carboxylicacid 42

methyl 2-[hydroxy(oxan-4-yl)- methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate 44

2-[(4-chlorophenyl)methyl]-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid46

2-(1-hydroxy-1-phenylethyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 45

methyl 2-(1-hydroxy-1- phenylethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate 47

methyl 2-[hydroxy-(2- methylpyrazol-3-yl)methyl]-1H-pyrrolo[3,2-b]pyridine- 7-carboxylate 49

methyl 2-[hydroxy-(1- methylpyrazol-4-yl)methyl]-1H-pyrrolo[3,2-b]pyridine- 7-carboxylate 51

methyl 2-(cyclopentylmethyl)- 1H-pyrrolo[3,2-b]pyridine- 7-carboxylate48

2-[hydroxy-(2-methylpyrazol-3- yl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 52

2-(cyclopentylmethyl)-1H- pyrrolo[3,2-b]pyridine- 7-carboxylic acid 53

methyl 2-(cyclohexylmethyl)-1H- pyrrolo[3,2-b]pyridine- 7-carboxylate 54

2-(cyclohexylmethyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 50

2-[hydroxy-(1-methylpyrazol-4- yl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 55

methyl 2-[[4-(trifluoro- methyl)phenyl]methyl]-1H-pyrrolo[3,2-b]pyridine- 7-carboxylate 56

2-[[4-(trifluoromethyl)- phenyl]methyl]-1H-pyrrolo-[3,2-b]-pyridine-7-carboxylic acid 57

methyl 2-(2-cyanoethyl)-1H- pyrrolo[3,2-b]pyridine- 7-carboxylate 58

2-(2-cyanoethyl)-1H-pyrrolo[3,2- b]-pyridine-7-carboxylic acid 59

2-[(4-methoxyphenyl)methyl]- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 60

2-[(4-fluorophenoxy)methyl]-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 61

methyl-2-[(4-methylphenoxy)- methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylate 62

2-[(4-methylphenoxy)methyl]- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 63

methyl 2-[(4-chlorophenoxy)- methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylate 64

2-[(4-chlorophenoxy)methyl]-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 66

2-[(2-methylphenoxy)methyl]- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 65

methyl 2-[(2-methyl- phenoxy)methyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 68

2-[[4-(trifluoromethyl)- phenoxy]methyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylic acid 67

methyl 2-[[4-(trifluoro- methyl)phenoxy]methyl]-1H-pyrrolo[3,2-b]pyridine-7- carboxylate 70

2-(2-phenylethyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 69

methyl 2-(2-phenylethyl)-1H- pyrrolo[3,2-b]pyridine- 7-carboxylate 72

2-[(2-chlorophenyl)-hydroxy- methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 71

methyl 2-[(2-chlorophenyl)- hydroxymethyl]-1H- pyrrolo[3,2-b]-pyridine-7-carboxylate 73

methyl 2-[(3-methylphenoxy)- methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate 74

2-[(3-methylphenoxy)methyl]- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 75

methyl 2-(2,3-dihydro-1- benzofuran-5-yloxymethyl)-1H-pyrrolo[3,2-b]pyridine-7- carboxylate 76

2-(2,3-dihydro-1-benzofuran-5- yloxymethyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 77

methyl 2-[(2-chloropehnyl)- methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate 78

2-[(2-chlorophenyl)methyl]-1H- pyrrolo[3,2-b]pyridin-7- carboxylic acid79

2-[(3-fluorophenoxy)methyl]-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 80

2-[(3-chlorophenoxy)methyl]-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 81

2-[(3,5-difluorophenoxy)methyl]- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 82

2-[(3,5-dimethylphenoxy)- methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 83

2-[(3,5-dichlorophenoxy)methyl]- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 84

2-(1-phenoxyethyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 85

2-(1-phenoxybutyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 86

2-(3-methyl-1-phenoxybutyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 87

methyl 2-[(2-chlorophenyl)- propoxymethyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 88

2-[(2-chlorophenyl)-propoxy- methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 89

methyl 2-[(2,4-dichloro- phenyl)methyl]-1H-pyrrolo-[3,2-b]-pyridine-7-carboxylate 90

2-[(2,4-dichlorophenyl)methyl]- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 91

methyl 2-(1-benzofuran-2-yl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylate92

2-(1-benzofuran-2-yl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 93

2-[(4-methoxyphenoxy)methyl]- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 94

2-[(2-chlorophenoxy)methyl]-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 95

2-[(2-fluroophenoxy)methyl]-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 96

2-[(2-chloro-4-fluoro- phenoxy)methyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylic acid 97

2-[(4-acetamidophenoxy)methyl]- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 98

2-[(4-cyanophenoxy)methyl]-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid99

2-(pyrrolidin-1-ylcarbonyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 100

methyl 2-[(4-fluorophenyl)- methyl]pyrrolo[3,2-b]pyridine-7- carboxylate101

2-[(4-fluorophenyl)methyl]- pyrrolo[3,2-b]pyridine-7- carboxylic acid102

methyl 2-[1-(4-fluorophenyl)-1- hydroxyethyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate 103

2-[1-(4-fluorophenyl)-1- hydroxyethyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 104

methyl 2-(1,2,3,4-tetrahydro- quinolylcarbonyl)pyrrolo[3,2-b]-pyridine-7-carboxylate 105

2-(1,2,3,4- tetrahydroquinolylcarbonyl)- pyrrolo[3,2-b]-pyridine-7-carboxylic acid 106

methyl 2-(indolinylcarbonyl)- pyrrolo[3,2-b]pyridine-7- carboxylate 107

2- (indolinylcarbonyl)pyrrolo[3,2-]- pyridine-7-carboxylic acid 108

methyl 2-(piperidyl-carbonyl)- pyrrolo[3,2-b]pyridine-7- carboxylate 109

2-(piperidylcarbonyl)pyrrolo[3,2- b]pyridine-7-carboxylic acid 110

2-[1-(4-fluorophenyl)ethyl]-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 111

methyl -2-(3-chloro-4- fluorobenzyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate 112

2-(3-chloro-4-fluorobenzyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 113

methyl 2-(4-chloro-3- fluorobenzyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate 114

2-(4-chloro-3-fluorobenzyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 115

methyl 2-[(3-phenylpyrrolidinyl)- carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylate 116

2-[(3-phenylpyrrolidinyl)- carbonyl]pyrrolo[3,2-b]pyridine- 7-carboxylicacid 117

methyl 2-[(4,4-dimethyl- piperidyl)carbonyl]pyrrolo[3,2-b]-pyridine-7-carboxylate 118

2-[(4,4-dimethylpiperidyl)- carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylic acid 119

methyl 2-[(3-phenylpiperidyl)- carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylate 120

2-[(3-phenylpiperidyl)- carbonyl]pyrrolo[3,2-b]pyridine- 7-carboxylicacid 121

methyl 2-(2-(1,2,3,4-tetrahydro- isoquinolylcarbonyl)pyrrolo-[3,2-b]-pyridine-7-carboxylate 122

2-(2-(1,2,3,4-tetrahydro- isoquinolylcarbonyl)pyrrolo-[3,2-b]pyridine-7-carboxylic acid 123

methyl 2-[(2,2-dimethyl- pyrrolidinyl)carbonyl]pyrrolo-[3,-b]-pyridine-7-carboxylate 124

2-[(2,2-dimethylpyrrolidinyl)- carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylic acid 125

methyl 2-(3,4-difluorobenzyl)- 1H-pyrrolo[3,2-b]pyridine-7- carboxylate126

2-(3,4-difluorobenzyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 127

methyl 2-(4-chloro-3- methoxybenzyl)-1H-pyrrolo-[3,2-b]-pyridine-7-carboxylate 128

2-(4-chloro-3-methoxybenzyl)- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 129

methyl 2-(3,4-dichlorobenzyl)- 1H-pyrrolo[3,2-b]pyridine-7- carboxylate130

2-(3,4-dichlorobenzyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid 131

methyl 2-(3,4-dichloro-5- fluorobenzyl)-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 132

2-(3,4-dichloro-5-fluorobenzyl)- 1H-pyrrolo[3,2-b]pyridine-7- carboxylicacid 133

methyl-2-(4-chloro-3- methylbenzyl)-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 134

2-(4-chloro-3-methylbenzyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylicacid 135

methyl 2-[4-chloro-3- (trifluoromethyl)benzyl]-1H-pyrrolo[3,2-b]pyridine- 7-carboxylate 136

2-[4-chloro-3-(trifluoro- methyl)benzyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylic acid 137

methyl 2-[4-chloro-3-(cyclo- propylmethoxy)benzyl]-1H-pyrrolo[3,2-b]pyridine- 7-carboxylate 138

2-[4-chloro-3-(cyclopropyl- methoxy)benzyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 139

methyl-2-[4-chloro-3-(2,2,2- trifluoroethoxy)benzyl]-1H-pyrrolo[3,2-b]pyridine- 7-carboxylate 140

2-[4-chloro-3-(2,2,2- trifluoroethoxy)benzyl]-1H-pyrrolo[3,2-b]pyridine-7- carboxylic acid 141

methyl-2-[4-chloro-3- (trifluoromethoxy)benzyl]-1H-pyrrolo[3,2-b]pyridin- 7-carboxylate 142

2-[4-chloro-3-(trifluoro- methoxy)benzyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylic acid 143

2-[4-chloro-benzyl]-N-methyl- 1H-pyrrolo[3,2-b]pyridine- 7-carboxamide144

2-[4-chloro-3-(trifluoro- methoxy)benzyl]-N-methyl-1H-pyrrolo-[3,2-b]pyridine- 7-carboxamide

In additional embodiments, the compound of Formula (I), (Ia), or (II) isselected from a compound provided in Table 2, or alkyl ester derivativethereof.

TABLE 2

Preparation of the Substituted Pyrrolopyridine Derivative Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Methods known to one of ordinary skill in the art are identified throughvarious reference books and databases. Suitable reference books andtreatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references toarticles that describe the preparation, include for example, “SyntheticOrganic Chemistry”, John Wiley & Sons, Inc., NY; Sandler et al.,“Organic Functional Group Preparations,” 2nd Ed., Academic Press, N Y,1983; House, “Modern Synthetic Reactions”, 2nd Ed., Benjamin, Inc. MenloPark, Calif. 1972; Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., JohnWiley & Sons, N Y, 1992; March, “Advanced Organic Chemistry: Reactions,Mechanisms & Structure”, 4th Ed., Wiley-Interscience, N Y, 1992.Additional suitable reference books and treatise that detail thesynthesis of reactants useful in the preparation of compounds describedherein, or provide references to articles that describe the preparation,include for example, Fuhrhop & Penzlin “Organic Synthesis: Concepts,Methods, Starting Materials”, 2nd, Revised, Enlarged Ed. (1994) JohnWiley & Sons ISBN: 3-527-29074-5; Hoffman, “Organic Chemistry,Intermediate Text” (1996) Oxford Univ. Press, ISBN 0-19-509618-5;Larock, “Comprehensive Organic Transformations: A Guide to FunctionalGroup Preparations” 2nd Ed. (1999) Wiley-VCH, ISBN: 0-471-19031-4;March, “Advanced Organic Chemistry: Reactions, Mechanisms, andStructure” 4th Ed. (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera,(editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN:3-527-29871-1; Patai, “Patai's 1992 Guide to the Chemistry of FunctionalGroups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, “OrganicChemistry” 7th Ed. (2000) John Wiley & Sons, ISBN: 0-471-19095-0;Stowell, “Intermediate Organic Chemistry” 2nd Ed. (1993)Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals:Starting Materials & Intermediates: Ullmann's Encyclopedia” (1999) JohnWiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions”(1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry ofFunctional Groups” John Wiley & Sons, in 73 volumes.

Specific and analogous reactants may also be identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the substituted pyrrolopyridine derivativecompounds described herein is Stahl & Wermuth “Handbook ofPharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

The substituted pyrrolopyridine derivative compounds are prepared by thegeneral synthetic routes described in Schemes 1 and 2.

Referring to Scheme 1, compound A and terminal alkyne compound B arecombined and treated under a variety of palladium-mediated Sonogashiracross-coupling conditions to form compound C. For example, the mixtureof compound A and an alkyne B can be subjected to conditions similar toprocedures described in literature (Tetrahedron Lett. 4467-4470; Org.Lett. 2006, 3307-10 (1975)) using various catalyst, co-catalyst, ligand,base, and solvent, at temperatures ranging from 40° C. to 100° C. Theazaindole compound D can be prepared by cycloisomerization of compound Cusing a base, such as KOtBu at 0° C., or catalyzed by CuI at temperatureranging from 100° C. to 140° C. Acid compound E can be prepared byhydrolysis of ester compound D using base, such as NaOH, or by otherconditions known in the art for ester hydrolysis.

Referring to Scheme 2, compound A and a ketone compound F are mixed andtreated to palladium-mediated direct annulation conditions to formcompound D. For example, the mixture of compound A and a ketone B can besubjected to conditions similar to procedures described in literature(Angew. Chem. Int. Ed. 2004, 4526-4528) using a Pd catalyst, ligand,acid, base, and solvent, at temperatures range up to 140° C.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Pharmaceutical Compositions

In certain embodiments, a substituted pyrrolopyridine derivativecompound as described herein is administered as a pure chemical. Inother embodiments, the substituted pyrrolopyridine derivative compoundas described herein is combined with a pharmaceutically suitable oracceptable carrier (also referred to herein as a pharmaceuticallysuitable (or acceptable) excipient, physiologically suitable (oracceptable) excipient, or physiologically suitable (or acceptable)carrier) selected on the basis of a chosen route of administration andstandard pharmaceutical practice as described, for example, inRemington: Science & Practice of Pharmacy (Gennaro, 21^(st) Ed. MackPub. Co., Easton, Pa. (2005)), the disclosure of which is herebyincorporated herein by reference, in its entirety.

Accordingly, provided herein is a pharmaceutical composition comprisingat least one substituted pyrrolopyridine derivative compound asdescribed herein, or a stereoisomer, pharmaceutically acceptable salt,hydrate, solvate, or N-oxide thereof, together with one or morepharmaceutically acceptable carriers. The carrier(s) (or excipient(s))is acceptable or suitable if the carrier is compatible with the otheringredients of the composition and not deleterious to the recipient(i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I), or apharmaceutically acceptable salt thereof.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (Ia), or apharmaceutically acceptable salt thereof.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (II), or apharmaceutically acceptable salt thereof.

In certain embodiments, the substituted pyrrolopyridine derivativecompound as described herein is substantially pure, in that it containsless than about 5%, or less than about 1%, or less than about 0.1%, ofother organic small molecules, such as contaminating intermediates orby-products that are created, for example, in one or more of the stepsof a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract.Suitable nontoxic solid carriers can be used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. (See, e.g., Remington: Science & Practice ofPharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

The dose of the composition comprising at least one substitutedpyrrolopyridine derivative compound as described herein may differ,depending upon the patient's (e.g., human) condition, that is, stage ofthe disease, general health status, age, and other factors that a personskilled in the medical art will use to determine dose.

Pharmaceutical compositions may be administered in a manner appropriateto the disease to be treated (or prevented) as determined by personsskilled in the medical arts. An appropriate dose and a suitable durationand frequency of administration will be determined by such factors asthe condition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome, such as more frequent complete or partial remissions, or longerdisease-free and/or overall survival, or a lessening of symptomseverity. Optimal doses may generally be determined using experimentalmodels and/or clinical trials. The optimal dose may depend upon the bodymass, weight, or blood volume of the patient.

Oral doses can typically range from about 1.0 mg to about 1000 mg, oneto four times, or more, per day.

Histone Demethylase

Chromatin is the complex of DNA and protein that makes up chromosomes.Histones are the major protein component of chromatin, acting as spoolsaround which DNA winds. Changes in chromatin structure are affected bycovalent modifications of histone proteins and by non-histone bindingproteins. Several classes of enzymes are known which can covalentlymodify histones at various sites.

Proteins can be post-translationally modified by methylation on aminogroups of lysines and guanidino groups of arginines or carboxymethylatedon aspartate, glutamate, or on the C-terminus of the protein.Post-translational protein methylation has been implicated in a varietyof cellular processes such as RNA processing, receptor mediatedsignaling, and cellular differentiation. Post-translational proteinmethylation is widely known to occur on histones, such reactions knownto be catalyzed by histone methyltransferases, which transfer methylgroups from S-adenyosyl methionine (SAM) to histones. Histonemethylation is known to participate in a diverse range of biologicalprocesses including heterochromatin formation, X-chromosomeinactivation, and transcriptional regulation (Lachner et al., (2003) J.Cell Sci. 116:2117-2124; Margueron et al., (2005) Curr. Opin. Genet.Dev. 15:163-176).

Unlike acetylation, which generally correlates with transcriptionalactivation, whether histone methylation leads to transcriptionactivation or repression depends on the particular site of methylationand the degree of methylation (e.g., whether a particular histone lysineresidue is mono-, di-, or tri-methylated). However, generally,methylation on H3K9, H3K27 and H4K20 is linked to gene silencing, whilemethylation on H3K4, H3K36, and H3K79 is generally associated withactive gene expression. In addition, tri- and di-methylation of H3K4generally marks the transcriptional start sites of actively transcribedgenes, whereas mono-methylation of H3K4 is associated with enhancersequences.

A “demethylase” or “protein demethylase,” as referred to herein, refersto an enzyme that removes at least one methyl group from an amino acidside chain. Some demethylases act on histones, e.g., act as a histone H3or H4 demethylase. For example, an H3 demethylase may demethylate one ormore of H3K4, H3K9, H3K27, H3K36 and/or H3K79. Alternately, an H4demethylase may demethylate histone H4K20. Demethylases are known whichcan demethylate either a mono-, di- and/or a tri-methylated substrate.Further, histone demethylases can act on a methylated core histonesubstrate, a mononucleosome substrate, a dinucleosome substrate and/oran oligonucleosome substrate, peptide substrate and/or chromatin (e.g.,in a cell-based assay).

The first lysine demethylase discovered was lysine specific demethylase1 (LSD1/KDM1), which demethylates both mono- and di-methylated H3K4 orH3K9, using flavin as a cofactor. A second class of Jumonji C (JmjC)domain containing histone demthylases were predicted, and confirmed whena H3K36 demethylase was found using a formaldehyde release assay, whichwas named JmjC domain containing histone demethylase 1 (JHDM1/KDM2A).

More JmjC domain-containing proteins were subsequently identified andthey can be phylogenetically clustered into seven subfamilies: JHDM1,JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY, and JmjC domain only.

JMJD2 Family

The JMJD2 family of proteins are a family of histone-demethylases knownto demethylate tri- and di-methylated H3-K9, and were the firstidentified histone tri-methyl demethylases. In particular, ectopicexpression of JMJD2 family members was found to dramatically decreaselevels of tri- and di-methylated H3-K9, while increasing levels ofmono-methylated H3-K9, which delocalized Heterochromatin Protein 1 (HP1)and reduced overall levels of heterochromatin in vivo. Members of theJMJD2 subfamily of jumonji proteins include JMJD2C and its homologuesJMJD2A, JMJD2B, JMJD2D and JMJD2E. Common structural features found inthe JMJD2 subfamily of Jumonji proteins include the JmjN, JmjC, PHD andTdr sequences.

JMJD2C, also known as GASC1 and KDM4C, is known to demethylatetri-methylated H3K9 and H3K36. Histone demethylation by JMJD2C occursvia a hydroxylation reaction dependent on iron and α-ketoglutarate,wherein oxidative decarboxylation of α-ketoglutarate by JMJD2C producescarbon dioxide, succinate, and ferryl and ferryl subsequentlyhydroxylates a methyl group of lysine H3K9, releasing formaldehyde.JMJD2C is known to modulate regulation of adipogenesis by the nuclearreceptor PPARγ and is known to be involved in regulation of self-renewalin embryonic stem cells.

JARID Family

As used herein, a “JARID protein” includes proteins in the JARID1subfamily (e.g., JARID1A, JARID1B, JARID1C and JARID1D proteins) and theJARID2 subfamily, as well as homologues thereof. A further descriptionand listing of JARID proteins can be found in Klose et al. (2006) NatureReviews/Genetics 7:715-727. The JARID1 family contains several conserveddomains: JmjN, ARID, JmjC, PHD and a C5HC2 zing finger.

JARID1A, also called KDM5A or RBP2, was initially found as a bindingpartner of retinoblastoma (R^(b)) protein. JARID1A was subsequentlyfound to function as a demethylase of tri- and di-methylated H3K4, andhas been found to promote cell growth, while inhibiting senescence anddifferentiation. For instance, abrogation of JARID1A from mouse cellsinhibits cell growth, induces senescence and differentiation, and causesloss of pluripotency of embryonic stem cells in vitro. JARID1A has beenfound to be overexpressed in gastric cancer and the loss of JARID1A hasbeen found to reduce tumorigenesis in a mouse cancer model.Additionally, studies have demonstrated that loss of the retinoblastomebinding protein 2 (RBP2) histone demethylase suppresses tumorigenesis inmice lacking Rb1 or Men1 (Lin et al. Proc. Natl. Acad. Sci. USA, Aug.16, 2011, 108(33),13379-86; doi: 10.1073/pnas.1110104108) and lead tothe conclusion that RBP2-inhibitory drugs would have anti-canceractivity.

JARID1B, also referred to as KDM5B and PLU1, was originally found inexperiments to discover genes regulated by the HER2 tyrosine kinase.JARID1B has consistently been found to be expressed in breast cancercell lines, although restriction of JARID1B has been found in normaladult tissues, with the exception of the testis. In addition, 90% ofinvasive ductal carcinomas have been found to express JARID1B. Inaddition, JARID1B has been found to be up-regulated in prostate cancers,while having more limited expression in benign prostate, and has alsobeen found to be up-regulated in bladder cancer and lung cancer (bothSCLC and NSCLC). JARID1B has also been found to repress tumor suppressorgenes such as BRCA1, CAV1 and 14-3-30, and knockdown of JARID1B wasfound to increase the levels of tri-methylated H3K4 at these genes.

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (Ia), or a pharmaceutically acceptablesalt thereof.

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (II), or a pharmaceutically acceptablesalt thereof.

In an additional embodiment is the method for inhibiting ahistone-demethylase enzyme, wherein the histone-demethylase enzymecomprises a JmjC domain. In an additional embodiment is the method forinhibiting a histone-demethylase enzyme, wherein the histone-demethylaseenzyme is selected from JARID1A, JARID1B, JMJD2C, or JMJD2A.

Methods of Treatment

Disclosed herein are methods of modulating demethylation in a cell or ina subject, either generally or with respect to one or more specifictarget genes. Demethylation can be modulated to control a variety ofcellular functions, including without limitation: differentiation;proliferation; apoptosis; tumorigenesis, leukemogenesis or otheroncogenic transformation events; hair loss; or sexual differentiation.For example, in particular embodiments, the invention provides a methodof treating a disease regulated by histone methylation and/ordemethylation in a subject in need thereof by modulating the activity ofa demethylase comprising a JmjC domain (e.g., a histone demethylase suchas a JHDM protein(s)).

In an additional embodiment is a method for treating cancer in subjectcomprising administering a composition comprising a compound of Formula(I), (Ia), or (II), or a pharmaceutically acceptable salt thereof.

In a further embodiment is the method for treating cancer in a subjectwherein the cancer is selected from prostate cancer, breast cancer,bladder cancer, lung cancer or melanoma.

In an additional embodiment is a method for inhibiting the growth of atumor comprising administering a composition comprising a compound ofFormula (I), (Ia), or (II), or a pharmaceutically acceptable saltthereof, wherein the tumor is characterized by a loss of retinoblastomagene (RB1) function.

In an additional embodiment is a method for inhibiting the growth of atumor comprising administering a composition comprising a compound ofFormula (I), (Ia), or (II), or a pharmaceutically acceptable saltthereof, wherein the tumor is characterized by a loss of multipleendocrine neoplasia type 1 gene (Men1) function.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

EXAMPLES I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants, J are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Example 1: 3-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

To a vial charged with 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (130mg, 0.8 mmol) in acetonitrile (2 mL) was added NCS (133.5 mg, 1.0 mmol).The reaction was allowed to stir at 70° C. for 2 hr. The reaction wasquenched with water and pH adjusted to ˜3 with HCl (1 N). Theprecipitate was filtered and washed successively with water, ethanol,and dried in vacuo to afford the title compound (79 mg, 40%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.66 (d, J=4.80 Hz, 1H), 7.82 (d,J=3.03 Hz, 1H), 8.56 (d, J=4.80 Hz, 1H), 11.54-11.87 (m, 1H), 13.90 (br.s., 1H). [M+H] calc'd for C₈H₅N₂O₂Cl, 197; found 197.

Example 2: 2-phenyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

Methyl 3-amino-2-chloroisonicotinate (187 mg, 1.0 mmol), Pd(PPh₃)₂Cl₂(35 mg, 0.05 mmol), CuI (38 mg, 0.20 mmol), TEA (278 μL, 2.0 mmol) andphenylacetylene (130 mg, 1.2 mmol) were suspended in DMF (2 mL). N₂ wasbubbled into the reaction for 2 min and it was allowed to stir at 100°C. for 16 hr. The reaction was concentrated in vacuo and purified bycolumn chromatography (0-50% gradient of EtOAc/Hex) to afford methyl3-amino-2-(phenylethynyl)pyridine-4-carboxylate (195 mg, 77%) as a brownfoam. [M+H] calc'd for C₁₄H₁₀N₂O₂, 239; found 239.

Methyl 3-amino-2-(phenylethynyl)pyridine-4-carboxylate (50 mg, 0.2 mmol)in NMP (1 mL) was added KO-t-Bu (67.5 mg, 0.6 mmol) and allowed to stirfor 2 hr. Water was added and the pH was adjusted to ˜3 with HCl (1N).The precipitate was filtered and the filter cake was successively washedwith water followed by ethanol to afford the title compound as a whitesolid (34 mg, 74%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 7.18 (s, 1H),7.38-7.63 (m, 5H), 8.02 (d, J=7.33 Hz, 2H), 8.36-8.62 (m, 1H). [M+H]calc'd for C₁₄H₁₀N₂O₂, 239; found 239.

Example 3: 2-(2-methylphenyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 64% yield using 2-ethynyltolueneaccording to the procedure for the preparation of Example 2. ¹H NMR (400MHz, DMSO-d₆): δ ppm 2.43 (s, 3H), 6.80 (s, 1H), 7.30-7.42 (m, 3H),7.45-7.66 (m, 2H), 8.49 (d, J=4.80 Hz, 1H), 11.21 (br. s., 1H), 13.66(br. s., 1H). [M+H] calc'd for C₁₅H₁₂N₂O₂, 253; found 253.

Example 4: methyl2-(2-hydroxypropan-2-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

Methyl 3-amino-2-chloroisonicotinate (186 mg, 1 mmol), PdCl₂(CH₃CN)₂(5.2 mg, 0.02 mmol), X-Phos (19 mg, 0.04 mmol), K₂CO₃ (278 mg, 2.0mmol), and 2-methyl-3-butyn-2-ol (130 mg, 1.2 mmol) in CH₃CN (2 mL) waspurged with N₂ for 2 min. The reaction was allowed to stir at 80° C. for16 hr. The reaction was concentrated in vacuo and purified by columnchromatography (0-50% gradient of EtOAc/Hex) to afford methyl3-amino-2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridine-4-carboxylate (191mg, 81%). [M+H] calc'd for C₁₂H₁₄N₂O₃, 235; found 235.

Methyl 3-amino-2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridine-4-carboxylate(191 mg, 0.82 mmol) and CuI (47.5 mg, 0.25 mmol) in DMF (2 mL) waspurged with N₂ for 2 min, and the reaction was allowed to stir at 110°C. for 2 hr. The reaction mixture was concentrated and purified bycolumn chromatography (0-50% gradient of EtOAc/Hex) to afford the titlecompound as an amorphous solid (172 mg, 74%). ¹H NMR (400 MHz, DMSO-d₆):δ ppm 2.43 (s, 3H), 6.80 (s, 1H), 7.307.42 (m, 3H), 7.45-7.66 (m, 2H),8.49 (d, J=4.80 Hz, 1H), 11.21 (br. s., 1H), 13.66 (br. s., 1H). [M+H]calc'd for C₁₂H₁₄N₂O₃, 235; found 235.

Example 5:2-(2-hydroxypropan-2-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

To methyl2-(2-hydroxypropan-2-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate (100mg, 0.45 mmol) in MeOH (1 mL) was added NaOH (75 μL, 1N), and thereaction stirred at 60° C. for 30 min. HCl (75 μL, 1N) was added atambient temperature to give a suspension. The solid was filtered andwashed successively with water followed by ethanol and dried in vacuo toafford the title compound (68 mg, 69%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.50 (s, 6H), 5.56 (br. s., 1H), 6.40 (s, 1H),7.41 (d, J=5.05 Hz, 1H), 8.33 (d, J=4.80 Hz, 1H), 10.30 (br. s., 1H).[M+H] calc'd for C₁₁H₁₂N₂O₃, 221; found 221.

Example 6: methyl 2-benzyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 60% yield using 3-phenyl-propyneaccording to the procedure for the preparation of Example 4. ¹H NMR (400MHz, CDCl₃): δ ppm 3.98 (s, 3H), 4.22 (s, 2H), 6.59-6.63 (m, 1H),7.27-7.42 (m, 5H), 7.55 (d, J=4.80 Hz, 1H), 8.50 (d, J=5.05 Hz, 1H),9.26 (br. s., 1H). [M+H] calc'd for C₁₆H₁₄N₂O₂, 267; found 267.

Example 7: 2-benzyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid, sodiumsalt

The title compound was prepared in 94% yield with methyl2-benzyl-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate according to theprocedure for the preparation of Example 5. The title compound (67 mg,0.27 mmol) was taken up in CH₃CN/water (1:1) and NaOH (293 μL, 1N) andlyophilized for 16 hr to afford the sodium salt. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 4.11 (s, 2H), 6.12 (d, J=2.02 Hz, 1H), 7.17 (d, J=4.80Hz, 2H), 7.21-7.31 (m, 4H), 8.08 (d, J=4.80 Hz, 1H), 10.66 (br. s., 1H).[M+H] calc'd for C₁₅H₁₂N₂O₂, 253; found 253.

Example 8: 2-propyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 28% yield using 1-pentyne accordingto the procedures for the preparation of Examples 4 and 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.84-0.97 (m, 3H), 1.67 (m, 2H), 6.52 (s, 1H),7.57-7.70 (m, 1H), 8.42-8.59 (m, 1H), 11.79 (br. s., 1H). [M+H] calc'dfor C₁₁H₁₂N₂O₂, 205; found 205.

Example 9:methyl-2-(hydroxymethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

Methyl 3-amino-2-chloroisonicotinate (1.04 g, 5.64 mmol), propargylalcohol (393 μL, 6.76 mmol), Pd(PPh₃)₂Cl₂ (198 mg, 0.28 mmol), CuI (28mg, 0.14 mmol), and TEA (2.84 g, 28.18 mmol) were combined inacetonitrile (20 mL). The reaction was purged with nitrogen for 2 minand then was stirred at 40° C. for 16 hr. The reaction was concentratedin vacuo and the residue suspended in dichloromethane and filtered. Thefiltrate was concentrated in vacuo and the residue purified by silicagel chromatography (PE/EA=3/1-1/1) to afford methyl3-amino-2-(3-hydroxyprop-1-yn-1-yl)pyridine-4-carboxylate (200 mg, 18%).¹H NMR (300 MHz, DMSO-d₆): δ 3.86 (3H, s), 4.39 (2H, d, J=8.0 Hz), 5.42(1H, t, J=8.0 Hz), 6.24 (2H, s), 7.55 (1H, d, J=6.4 Hz), 7.81 (1H, d,J=5.6 Hz). [M+H] Calc'd for C₁₀H₁₀N₂O₃, 207; Found, 207.

Methyl 3-amino-2-(3-hydroxyprop-1-yn-1-yl)pyridine-4-carboxylate (476mg, 2.31 mmol), CaCO₃ (427 mg, 4.27 mmol), CuI (203 mg, 1.07 mmol), andDMF (10 mL) was purged with nitrogen and stirred for 1 hr at 120° C. Thereaction was concentrated in vacuo and the residue suspended indichloromethane and filtered. The filtrate was concentrated in vacuo andthe residue purified by silica gel chromatograph (PE/EA=3/1-1/1) toafford title the compound (40 mg, 20%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.98(3H, s), 4.72 (2H, d, J=6.8 Hz), 5.37 (1H, t, J=8.4 Hz), 6.57 (1H, t,J=1.6 Hz), 7.52 (1H, d, J=6.8 Hz), 8.42 (1H, d, J=6.4 Hz), 11.11 (1H,s). LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=1.970 min. [M+H] Calc'd for C₁₀H₁₀N₂O₃, 207; Found, 207.

Example 10: 2-(hydroxymethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 37% yield usingmethyl-2-(hydroxymethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 4.76 (s, 2H), 6.67 (s, 1H), 7.68 (d, J=5.31 Hz,1H), 8.53 (d, J=5.31 Hz, 1H), 11.63 (br. s., 1H). [M+H] calc'd forC₉H₈N₂O₃, 193; found 193.

Example 11: methyl 2-cyclopropyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 54% yield using cyclopropylacetyleneaccording to the procedure for the preparation of Example 4. ¹H NMR (400MHz, CDCl₃): δ ppm 0.79-0.98 (m, 2H), 1.00-1.17 (m, 2H), 1.96-2.21 (m,1H), 4.02 (s, 3H), 6.38 (s, 1H), 7.51 (d, J=5.05 Hz, 1H), 8.47 (d,J=5.05 Hz, 1H), 9.38 (br. s., 1H). [M+H] calc'd for C₁₂H₁₂N₂O₂, 217;found 217.

Example 12: 2-cyclopropyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 85% yield using methyl2-cyclopropyl-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate according to theprocedure for the preparation of Example 5. ¹H NMR (400 MHz, DMSO-d₆): δppm 0.99 (dd, J=4.80, 2.27 Hz, 1H), 1.21 (dd, J=8.34, 2.53 Hz, 1H), 6.36(d, J=1.77 Hz, 1H), 7.69 (d, J=5.56 Hz, 1H), 8.50 (d, J=5.56 Hz, 1H),12.31 (br. s., 1H). [M+H] calc'd for C₁₁H₁₀N₂O₂, 203; found 203.

Example 13: methyl2-(1-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 62% yield using 1-ethynylcyclohexanolaccording to the procedure for the preparation of example 4. ¹H NMR (400MHz, CDCl₃): δ ppm 1.61-2.37 (m, 11H), 4.03 (s, 3H), 6.59 (d, J=2.27 Hz,1H), 7.54-7.78 (m, 1H), 8.51 (d, J=4.80 Hz, 1H), 9.73 (br. s., 1H).[M+H] calc'd for C₁₅H₁₈N₂O₃, 275; found 275.

Example 14:2-(1-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 85% yield using methyl2-(1-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.46-1.59 (m, 2H), 1.59-1.96 (m, 8H), 5.36 (s, 1H),6.50 (d, J=2.02 Hz, 1H), 7.49 (d, J=5.05 Hz, 1H), 8.41 (d, J=4.80 Hz,1H), 10.32 (br. s., 1H), 13.81 (br. s., 1H). [M+H] calc'd forC₁₄H₁₆N₂O₃, 261; found 261.

Example 15: methyl2-(4-methoxy-2-methylphenyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 23% yield using1-ethynyl-4-methoxy-2-methylbenzene according to the procedure for thepreparation of Example 4. ¹H NMR (400 MHz, CDCl₃): δ ppm 2.52 (s, 3H),3.87 (s, 3H), 4.05 (s, 3H), 6.86-7.00 (m, 3H), 7.48 (d, J=8.08 Hz, 1H),7.63 (d, J=5.05 Hz, 1H), 8.56 (d, J=5.31 Hz, 1H), 9.61 (br. s., 1H).[M+H] calc'd for C₁₇H₁₆N₂O₃, 297; found 297.

Example 16:2-(4-methoxy-2-methylphenyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 95% yield using methyl2-(4-methoxy-2-methyl-phenyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 2.42 (s, 3H), 3.81 (s, 3H), 6.72 (s, 1H), 6.85-7.02(m, 2H), 7.50 (dd, J=13.52, 6.69 Hz, 2H), 8.45 (d, J=4.80 Hz, 1H), 11.02(br. s., 1H), 13.59-13.76 (m, 1H). [M+H] calc'd for C₁₆H₁₄N₂O₃, 283;found 283.

Example 17: (1)-methyl2-(1-hydroxyethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 9% yield using (±)-propyn-3-olaccording to the procedure for the preparation of Example 9. ¹H NMR (400MHz, CDCl₃): δ ppm 1.68 (3H, d, J=6.4 Hz), 4.02 (3H, s), 5.18 (1H, q,J=6.4 Hz), 6.61 (1H, s), 7.69 (1H, d, J=4.8 Hz), 8.52 (1H, d, J=4.8 Hz),9.68 (1H, s). LCMS (mobile phase: 5-60% Acetonitrile-Water-0.02% NH₄Ac):purity is >95%, Rt=2.852 min. [M+H] calc'd for C₁₁H₁₂N₂O₃, 221; found221.

Example 18:(±)-2-(1-hydroxyethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 68% yield using (±)-methyl2-(1-hydroxyethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate according tothe procedure for the preparation of Example 5. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.49 (3H, d, J=6.4 Hz), 5.00 (1H, m), 5.50 (1H, s), 6.51(1H, d, J=2.0 Hz), 7.49 (1H, d, J=5.2 Hz), 8.41 (1H, d, J=4.8 Hz), 10.80(1H, s). LCMS (mobile phase: 0-60% Acetonitrile-Water-0.02% NH₄Ac):purity is >95%, Rt=2.688 min. [M+H] calc'd for C₁₀H₁₀N₂O₃, 207; found207.

Example 19: (±)-methyl2-[hydroxy(phenyl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 3% yield using(±)-1-phenyl-2-propyn-1-ol according to the procedure for thepreparation of Example 9. ¹H NMR (400 MHz, CDCl₃): δ ppm 3.96 (3H, s),6.06 (1H, s), 6.54 (1H, s), 7.27-7.31 (3H, m), 7.33-7.40 (2H, m), 7.57(1H, d, J=5.2 Hz), 8.42 (1H, d, J=5.2 Hz), 9.71 (1H, s). LCMS (mobilephase: 10-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.978min. [M+H] calc'd for C₁₆H₁₄N₂O₃, 283; found 283.

Example 20:(±)-2-[hydroxy(phenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 68% yield using (±)-methyl2-[hydroxy(phenyl)-methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 6.05 (1H, d, J=4.0 Hz), 6.20 (1H, d, J=4.8 Hz),6.43 (1H, d, J=1.2 Hz), 7.25-7.29 (1H, m), 7.33-7.37 (2H, m), 7.46-7.51(3H, m), 8.42 (1H, d, J=4.8 Hz), 10.94 (1H, s). LCMS (mobile phase:5-60% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.217 min.[M+H] calc'd for C₁₅H₁₂N₂O₃, 269; found 269.

Example 21: (1)-Methyl2-[hydroxy-(3-methylphenyl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 27% yield using(±)-1-(3-methylphenyl)prop-2-yn-1-ol according to the procedure for thepreparation of example 4. ¹H NMR (400 MHz, CDCl₃): δ ppm 2.36 (s, 4H),4.02 (s, 3H), 6.08 (s, 1H), 6.56-6.63 (m, 1H), 7.14-7.20 (m, 1H),7.28-7.34 (m, 2H), 7.61 (d, J=5.05 Hz, 1H), 8.51 (d, J=5.05 Hz, 1H),9.68 (br. s., 1H). [M+H] calc'd for C₁₇H₁₆N₂O₃, 297; found 297.

Example 22:(±)-2-[hydroxy-(3-methylphenyl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 90% yield using (±)-methyl2-[hydroxy-(3-methyl-phenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 2.29 (s, 3H), 6.00 (d, J=5.56 Hz, 1H), 6.15 (d,J=5.05 Hz, 1H), 6.39-6.50 (m, 1H), 7.04-7.13 (m, 1H), 7.24 (s, 3H), 7.48(s, 1H), 8.40 (d, J=4.80 Hz, 1H), 10.86 (br. s., 1H), 13.75 (br. s.,1H). [M+H] calc'd for C₁₆H₁₄N₂O₃, 283; found 283.

Example 23: (±)-methyl2-[hydroxy-(3-methoxyphenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 27% yield using(±)-1-(3-methoxyphenyl)prop-2-yn-1-ol according to the procedure for thepreparation of Example 4. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.81 (s, 3H),4.03 (s, 3H), 6.10 (s, 1H), 6.65 (s, 1H), 6.85-6.95 (m, 1H), 6.99-7.07(m, 2H), 7.29-7.36 (m, 2H), 7.65 (d, J=5.31 Hz, 1H), 8.51 (d, J=5.31 Hz,1H), 9.77 (br. s., 1H). [M+H] calc'd for C₁₇H₁₆N₂O₄, 313; found 313.

Example 24:(±)-2-[hydroxy-(3-methoxyphenyl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 90% yield using (±)-methyl2-[hydroxy-(3-methoxy-phenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.74 (s, 3H), 6.01 (d, J=5.31 Hz, 1H), 6.19 (d,J=5.56 Hz, 1H), 6.43 (s, 1H), 6.83 (dd, J=8.08, 2.53 Hz, 1H), 6.98-7.13(m, 2H), 7.26 (t, J=7.83 Hz, 1H), 7.40-7.58 (m, 1H), 8.40 (d, J=5.05 Hz,1H), 10.89 (br. s., 1H), 13.77 (br. s., 1H). [M+H] calc'd forC₁₆H₁₄N₂O₄, 299; found 299.

Example 25: (1)-methyl2-(1-hydroxypropyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 3% yield using (±)-1-pentyn-3-olaccording to the procedure for the preparation of Example 9. ¹H NMR (400MHz, CDCl₃): δ 0.94 (3H, t, J=7.2 Hz), 1.84-1.88 (2H, m), 3.62 (1H, bs),3.94 (3H, s), 4.85 (1H, t, J=5.6 Hz), 6.46 (1H, s), 7.49 (1H, s), 8.36(1H, s), 9.74 (1H, s). LCMS (mobile phase: 10-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.523 min. [M+H]calc'd for C₁₂H₁₄N₂O₃, 235; found 235.

Example 26:(±)-2-(1-hydroxypropyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 50% yield using (±)-methyl2-(1-hydroxypropyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate according tothe procedure for the preparation of Example 5. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 0.92 (3H, t, J=7.2 Hz), 1.72-1.89 (2H, m), 4.76-4.81(1H, m), 5.43 (1H, d, J=5.6 Hz), 6.51 (1H, d, J=2.0 Hz), 7.49 (1H, d,J=5.2 Hz), 8.40 (1H, d, J=5.2 Hz), 10.75 (1H, s). LCMS (mobile phase:0-60% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.887 min.[M+H] calc'd for C₁₁H₁₂N₂O₃, 221; found 221.

Example 27:2-(1-hydroxycyclopentyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 37% yield using1-ethynylcyclopropanol according to the procedure for the preparation ofExamples 4 and 5. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.71-2.15 (m, 8H),5.43 (s, 1H), 6.52 (d, J=1.77 Hz, 1H), 7.49 (d, J=4.80 Hz, 1H), 8.42(br. s., 1H), 10.40 (br. s., 1H), 13.81 (br. s., 1H). [M+H] calc'd forC₁₃H₁₄N₂O₃, 247; found 247.

Example 28: methyl 2-cyclopentyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 40% yield using 1-ethynylcyclopentaneaccording to the procedure for the preparation of Example 4. ¹H NMR (400MHz, CDCl₃): δ ppm 1.76-1.91 (m, 6H), 2.12-2.27 (m, 2H), 3.21-3.35 (m,1H), 4.04 (s, 3H), 6.59 (d, J=1.01 Hz, 1H), 7.57 (d, J=5.05 Hz, 1H),8.48 (d, J=5.05 Hz, 1H), 9.28-9.55 (m, 1H). [M+H] calc'd for C₁₄H₁₆N₂O₂,245; found 245.

Example 29: 2-cyclopentyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 83% yield using2-cyclopentyl-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid according toprocedure for the preparation of Example 5. ¹H NMR (400 MHz, DMSO-d₆): δppm 1.56-1.84 (m, 6H), 1.98-2.20 (m, 2H), 3.36-3.42 (m, 1H), 6.41 (s,1H), 7.39-7.49 (m, 1H), 7.43 (d, J=4.55 Hz, 1H), 8.35 (d, J=4.80 Hz,1H), 11.03 (br. s., 1H), 13.61 (br. s., 1H). [M+H] calc'd forC₁₃H₁₄N₂O₂, 231; found 231.

Example 30: (1)-methyl2-(1-hydroxy-2-methylpropyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 7% yield using(±)-4-methyl-pentyn-3-ol according to the procedure for the preparationof Example 9. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.93 (6H, d, J=6.8 Hz),2.04-2.11 (1H, m), 3.98 (3H, s), 4.74 (1H, d, J=6.0 Hz), 6.58 (1H, d,J=2.0 Hz), 7.56 (1H, d, J=5.2 Hz), 8.43 (1H, d, J=5.2 Hz), 9.70 (1H, s).LCMS (mobile phase: 10-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=2.826 min. [M+H] calc'd for C₁₃H₁₆N₂O₃, 249; found 249.

Example 31:(±)-2-(1-hydroxy-2-methylpropyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 30% yield using (±)-methyl2-(1-hydroxy-2-methylpropyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.88 (6H, d, J=6.8 Hz), 2.03-2.08 (1H, m),4.63-4.64 (1H, m), 5.42-5.44 (1H, m), 6.52 (1H, d, J=2.0 Hz), 7.50 (1H,d, J=5.2 Hz), 8.42 (1H, d, J=5.2 Hz), 10.76 (1H, s). LCMS (mobile phase:0-60% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.175 min.[M+H] calc'd for C₁₂H₁₄N₂O₃, 235; found 235.

Example 32: (1)-methyl2-[cyclopropyl(hydroxy)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 7% yield using(±)-3-cyclopropylpropyn-3-ol according to the procedure for thepreparation of Example 9. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.57-0.65 (2H,m), 0.76-0.83 (2H, m), 1.39-1.46 (1H, m), 4.09 (3H, s), 4.37 (1H, d,J=8.4 Hz), 6.80 (1H, s), 7.68 (1H, bs), 8.59 (1H, br), 9.81 (1H, s).LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=2.555 min. [M+H] calc'd for C₁₃H₁₄N₂O₃, 247; found 247.

Example 33:(±)-2-[cyclopropyl(hydroxy)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 30% yield using methyl2-[cyclopropyl(hydroxy)-methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.42-0.53 (4H, m), 1.26-1.30 (1H, m), 4.31 (1H, t,J=6.8 Hz), 5.53 (1H, d, J=5.6 Hz), 6.57 (1H, d, J=2.0 Hz), 7.50 (1H, d,J=4.8 Hz), 8.42 (1H, d, J=5.2 Hz), 10.68 (1H, s). LCMS (mobile phase:0-60% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.931 min.[M+H] calc'd for C₁₂H₁₂N₂O₃, 233; found 233.

Example 34:2-[(3-methoxyphenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

A mixture containing methyl2-[hydroxy-(3-methoxyphenyl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate(31 mg, 0.1 mmol), Et₃SiH (160 μL, 1 mmol), and TFA (149 μL, 2 mmol) wasstirred at 60° C. for 16 hr. The reaction was concentrated in vacuo andpurified by column chromatography (0%-50% EtOAc/Hex) to affordmethyl-2-[(3-methoxyphenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylate,which was converted to the title compound (21 mg, 70%) according toprocedure for Example 5. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.66 (s, 4H),4.12 (s, 2H), 6.30 (s, 1H), 6.73 (d, J=8.34 Hz, 1H), 6.79-6.95 (m, 3H),7.15 (t, J=7.83 Hz, 1H), 7.39 (d, J=4.80 Hz, 1H), 8.30 (d, J=4.55 Hz,1H), 11.19 (br. s., 1H), 13.60 (br. s., 1H). [M+H] calc'd forC₁₆H₁₄N₂O₃, 283; found 283.

Example 35: methyl2-[(3-methylphenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 74% yield using methyl2-[hydroxy-(3-methylphenyl)-methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 34. ¹H NMR(400 MHz, CDCl₃): δ ppm 2.33 (s, 3H), 3.97 (s, 3H), 4.16 (s, 2H),6.47-6.75 (m, 1H), 7.07 (s, 3H), 7.17-7.33 (m, 1H), 7.50-7.70 (m, 1H),8.40-8.83 (m, 1H), 9.18-9.49 (m, 1H). [M+H] calc'd for C₁₇H₁₆N₂O₂, 281;found 283.

Example 36:2-[(3-methylphenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 98% yield using methyl2-[(3-methylphenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 2.27 (s, 3H), 4.13-4.24 (m, 2H), 6.35 (s, 1H), 7.03(d, J=7.33 Hz, 1H), 7.08-7.27 (m, 4H), 7.45 (d, J=5.05 Hz, 1H), 8.37 (d,J=5.05 Hz, 1H), 11.25 (br. s., 1H), 13.65 (br. s., 1H). [M+H] calc'd forC₁₆H₁₄N₂O₂, 267; found 267.

Example 37: (1)-methyl2-(2-cyclopropyl-1-hydroxyethyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

A solution of 2-cyclopropylacetaldehyde (6.0 g, 71 mmol) in 15 mL THFwas added to a solution of ethynylmagnesium bromide (0.5 M, 214 mL, 107mmol) at 0° C. After 1.5 hr, saturated NH₄Cl solution (75 mL) was addedthe mixture was extracted with EtOAc. The organic layers weresuccessively washed water, brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography (EA/PE=1/5) toafford (±)-4-cyclopropylbutyn-3-ol (700 mg, 9%). ¹H NMR (400 MHz,CDCl₃): δ ppm 0.03-0.17 (2H, m), 0.31-0.37 (2H, m), 0.71-0.76 (1H, m),1.42-1.57 (2H, m), 2.33 (1H, d, J=2.4 Hz), 4.29-4.32 (1H, m).

The title compound was prepared in 6% yield using(±)-4-cyclopropylbutyn-3-ol according to the procedure for thepreparation of Example 9. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.15-0.21 (2H,m), 0.48-0.58 (2H, m), 0.82-0.86 (1H, m), 1.85 (2H, t, J=6.8 Hz), 4.04(3H, s), 5.12 (1H, t, J=6.8 Hz), 6.62 (1H, s), 7.61 (1H, bs), 8.52 (1H,bs), 9.75 (1H, s). LCMS (mobile phase: 10-95% Acetonitrile-Water-0.02%NH₄Ac): purity is >95%, Rt=2.869 min. [M+H] calc'd for C₁₄H₁₆N₂O₃, 261;found 261.

Example 38:(±)-2-(2-cyclopropyl-1-hydroxyethyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 32% yield using (±)-methyl2-(2-cyclopropyl-1-hydroxyethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.05-0.15 (2H, m), 0.35-0.42 (2H, m), 0.85-0.89(1H, m), 1.51-1.57 (1H, m), 1.80-1.87 (1H, m), 5.01-5.04 (1H, m), 6.78(1H, s), 7.82 (1H, d, J=5.6 Hz), 8.63 (1H, d, J=3.6 Hz), 11.95 (1H, s).LCMS (mobile phase: 0-60% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=3.313 min. [M+H] calc'd for C₁₃H₁₄N₂O₃, 247; found 247.

Example 39: 2-(phenoxymethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 1% yield using phenylpropargyletheraccording to the procedure for the preparation of Examples 4 and 5. ¹HNMR (400 MHz, DMSO-d₆): δ ppm 5.33 (s, 2H), 6.74 (s, 1H), 6.90-6.99 (m,1H), 7.05 (d, J=8.59 Hz, 2H), 7.29-7.37 (m, 2H), 7.55 (d, J=4.80 Hz,1H), 8.45 (d, J=4.80 Hz, 1H), 11.50 (br. s., 1H), 13.75 (br. s., 1H).[M+H] calc'd for C₁₅H₁₂N₂O₃, 269; found 269.

Example 40: methyl2-(methoxymethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 17% yield using methylpropargyletheraccording to the procedure for the preparation of Example 4. ¹H NMR (400MHz, CDCl₃): δ ppm 3.45-3.50 (m, 3H), 4.07 (s, 3H), 4.73 (s, 2H), 6.84(br. s., 1H), 7.68-7.75 (m, 1H), 8.55 (d, J=5.31 Hz, 1H), 9.70-9.89 (m,1H). [M+H] calc'd for C₁₁H₁₂N₂O₃, 221; found 221.

Example 41: 2-(methoxymethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 26% yield using methyl2-(methoxymethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate according tothe procedure for the preparation of Example 5. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 3.34 (s, 2H), 4.65 (s, 2H), 6.55-6.67 (m, 1H), 7.52 (d,J=4.80 Hz, 1H), 8.43 (d, J=4.80 Hz, 1H), 11.23 (br. s., 1H), 13.72 (br.s., 1H). [M+H] calc'd for C₁₀H₁₀N₂O₃, 207; found 207.

Example 42: (1)-methyl2-[hydroxy(oxan-4-yl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 32% yield using(±)-1-(oxan-4-yl)-1-prop-2-yn-1-ol according to the procedure for thepreparation of Example 9. ¹H NMR (400 MHz, CDCl₃): δ ppm 1.47-1.57 (3H,m), 1.86-1.89 (1H, m), 2.03-2.10 (1H, m), 3.39-3.46 (2H, m), 3.98-4.07(2H, m), 4.09 (3H, s), 4.82 (1H, d, J=6.8 Hz), 6.64 (1H, s), 7.65 (1H,d, J=4.8 Hz), 8.55 (1H, d, J=4.4 Hz), 9.75 (1H, s). LCMS (mobile phase:10-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.433 min.[M+H] calc'd for C₁₅H₁₈N₂O₄, 291; found 291.

Example 43:(±)-2-[hydroxy(oxan-4-yl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 54% yield (±)-methyl2-[hydroxy(oxan-4-yl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, CD₃OD): δ ppm 1.30-1.33 (1H, m), 1.43-1.60 (3H, m), 1.94-2.01 (1H,m), 3.26-3.38 (2H, m), 3.82-3.89 (2H, m), 4.75 (1H, d, J=6.0 Hz), 6.67(1H, s), 7.80 (1H, d, J=5.6 Hz), 8.41 (1H, d, J=5.6 Hz). LCMS (mobilephase: 0-60% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.873min. [M+H] calc'd for C₁₄H₁₆N₂O₄, 277; found 277.

Example 44:2-[(4-chlorophenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 4% yield using1-chloro-4-(prop-2-yn-1-yl)benzene according to the procedure for thepreparation of Examples 4 and 5. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 4.22(s, 2H), 6.37 (s, 1H), 7.37 (s, 4H), 7.46 (d, J=4.80 Hz, 1H), 8.37 (d,J=4.80 Hz, 1H), 11.31 (br. s., 1H), 13.61-13.73 (m, 1H). [M+H] calc'dfor C₁₅H₁₁N₂O₂Cl, 287; found 287.

Example 45: (1)-methyl2-(1-hydroxy-1-phenylethyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 31% yield using(±)-2-phenyl-3-butyn-2-ol according to the procedure for the preparationof example 4. ¹H NMR (400 MHz, CDCl₃): δ ppm 2.09 (s, 3H), 4.01 (s, 3H),6.77-6.89 (m, 1H), 7.28-7.41 (m, 5H), 7.45-7.55 (m, 3H), 7.65 (d, J=5.05Hz, 1H), 8.51 (d, J=5.05 Hz, 1H), 9.69 (br. s., 1H). [M+H] calc'd forC₁₇H₁₆N₂O₃, 297; found 297.

Example 46:(±)-2-(1-hydroxy-1-phenylethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 84% yield using (±)-methyl2-(1-hydroxy-1-phenylethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.89 (s, 3H), 6.36 (s, 1H), 6.68 (d, J=2.02 Hz,1H), 7.20-7.26 (m, 1H), 7.32 (t, J=7.58 Hz, 2H), 7.42 (d, J=7.33 Hz,2H), 7.51 (d, J=4.80 Hz, 1H), 8.45 (s, 1H), 10.28 (br. s., 1H), 13.80(br. s., 1H). [M+H] calc'd for C₁₆H₁₄N₂O₃, 283; found 283.

Example 47: (±)-methyl2-[hydroxy-(2-methylpyrazol-3-yl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 2% yield using1-methyl-1H-pyrazole-5-carbaldehyde according to the procedure for thepreparation of Example 37. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.86 (3H,s), 3.97 (3H, s), 5.93 (1H, d, J=1.6 Hz), 6.19 (1H, d, J=6.4 Hz), 6.34(1H, d, J=6.4 Hz), 6.59 (1H, d, J=1.2 Hz), 7.29 (1H, d, J=2.0 Hz), 7.56(1H, d, J=4.8 Hz), 8.43 (1H, d, J=4.8 Hz), 11.14 (1H, s). LCMS (mobilephase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.514min. [M+H] calc'd for C₁₄H₁₄N₄O₃, 287; found 287.

Example 48:(±)-2-[hydroxy-(2-methylpyrazol-3-yl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 65% yield using (±)-methyl2-[hydroxy-(2-methylpyrazol-3-yl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, CD₃OD): δ ppm 3.93 (3H, s), 6.16 (1H, d, J=1.6 Hz), 6.32 (1H, s),6.65 (1H, d, J=0.8 Hz), 7.42 (1H, d, J=1.6 Hz), 7.80 (1H, d, J=5.2 Hz),7.48 (1H, d, J=4.8 Hz). LCMS (mobile phase: 0-60%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.762 min. [M+H]calc'd for C₁₃H₁₂N₄O₃, 273; found 273.

Example 49: (±)-methyl2-[hydroxy-(1-methylpyrazol-4-yl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 3% yield using1-methyl-1H-pyrazole-4-carbaldehyde according to the procedure for thepreparation of Example 37. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.78 (3H,s), 3.98 (3H, s), 5.91 (1H, d, J=7.2 Hz), 5.97 (1H, d, J=6.0 Hz), 6.51(1H, d, J=1.6 Hz), 7.38 (1H, s), 7.52 (1H, d, J=4.8 Hz), 7.55 (1H, s),8.43 (1H, d, J=4.8 Hz), 10.96 (1H, s). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.407 min. [M+H]calc'd for C₁₄H₁₄N₄O₃, 287; found 287.

Example 50:(±)-2-[hydroxy-(1-methylpyrazol-4-yl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 70% yield using (±)-methyl2-[hydroxy-(1-methylpyrazol-4-yl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.78 (3H, s), 6.07 (1H, s), 6.72 (1H, s), 7.39 (1H,s), 7.58 (1H, s), 7.80 (1H, d, J=5.6 Hz), 8.62 (1H, d, J=5.6 Hz), 11.87(1H, s). LCMS (mobile phase: 0%-60% Acetonitrile-Water-0.02% NH₄Ac):purity is >95%, Rt=2.686 min. [M+H] calc'd for C₁₃H₁₂N₄O₃, 273; found273.

Example 51: methyl2-(cyclopentylmethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 8% yield usingprop-2-ynyl-cyclopentane according to the procedure for the preparationof Example 9. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.25-1.29 (2H, m),1.50-1.54 (2H, m), 1.59-1.65 (2H, m), 1.69-1.75 (2H, m), 2.27-2.34 (1H,m), 2.85 (2H, d, J=7.2 Hz), 3.98 (3H, s), 6.43 (1H, d, J=2.0 Hz), 7.46(1H, d, J=4.4 Hz), 8.38 (1H, d, J=5.2 Hz), 11.10 (1H, s). LCMS (mobilephase: 10%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.929min. [M+H] Calc'd for C₁₅H₁₈N₂O₂, 259; Found, 259.

Example 52: 2-(cyclopentylmethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 44% yield using methyl2-(cyclopentylmethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate accordingto the procedure for the preparation of Example 5. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.22-1.28 (2H, m), 1.47-1.75 (6H, m), 2.25-2.32 (1H, m),2.84 (2H, d, J=7.2 Hz), 6.40 (1H, s), 7.44 (1H, d, J=4.8 Hz), 8.36 (1H,d, J=3.6 Hz), 11.06 (1H, s), 13.59 (1H, br). LCMS (mobile phase: 0-60%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=4.194 min. [M+H]calc'd for C₁₄H₁₆N₂O₂, 245; found 245.

Example 53: methyl2-(cyclohexylmethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 24% yield usingprop-2-ynyl-cyclohexane according to the procedure for the preparationof Example 9. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.94-1.04 (2H, m),1.12-1.25 (3H, m), 1.61-1.75 (6H, m), 2.74 (2H, d, J=7.2 Hz), 3.98 (3H,s), 6.40 (1H, d, J=2.0 Hz), 7.46 (1H, d, J=5.2 Hz), 8.38 (1H, d, J=4.8Hz), 11.10 (1H, s). [M+H] calc'd for C₁₆H₂₀N₂O₂, 273; found 273.

Example 54: 2-(cyclohexylmethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 42% yield using methyl2-(cyclohexylmethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate accordingto the procedure for the preparation of Example 5. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 0.93-0.99 (2H, m), 1.16-1.24 (3H, m), 1.60-1.72 (6H, m),2.74 (2H, d, J=7.0 Hz), 6.38 (1H, s), 7.45 (1H, d, J=5.2 Hz), 8.37 (1H,d, J=3.2 Hz), 11.15 (1H, s). LCMS (mobile phase: 0-60%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=4.404 min. [M+H]calc'd for C₁₅H₁₈N₂O₂, 259; found 259.

Example 55: methyl2-[[4-(trifluoromethyl)phenyl]methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

4-(trifluoromethyl)benzaldehyde (2.73 mL, 20 mmol) was added dropwiseinto a round-bottom flask containing a solution of ethynyl Mg bromide(50 mL, 25 mmol) in THF at 0° C. After 30 min the reaction was quenchedwith aq. NH₄Cl. The mixture was taken up in EtOAc and washedsuccessively with water, brine, and dried with Na₂SO₄. The organiclayers were concentrated in vacuo to afford1-[4-trifuoromethyl)phenyl]prop-2-yn-1-ol as a yellow oil (3.65 g, 91%).

To a vial containing 1-[4-trifuoromethyl)phenyl]prop-2-yn-1-ol (1.65 g,8.25 mmol) was added Et₃SiH (3.98 mL, 25 mmol) followed by TFA (3.83 mL,50 mmol). The reaction was capped and allowed to stir at 60° C. for 16hr. The reaction was concentrated in vacuo and the residue purified bycolumn chromatography (0-10% EtOAc/hexanes gradient, 12 g silica) toafford 1-(prop-2-yn-1yl)-4-(trifluoromethyl)benzene (325 mg, 21%) as aclear oil.

The title compound was prepared in 17% yield using1-(prop-2-yn-1yl)-4-(trifluoro-methyl)benzene according to the procedurefor the preparation of Example 4. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.00(s, 3H), 4.28 (s, 2H), 6.59-6.68 (m, 1H), 7.39 (d, J=8.08 Hz, 3H),7.56-7.67 (m, 4H), 8.53 (d, J=4.80 Hz, 1H), 9.33 (br. s., 1H). [M+H]calc'd for C₁₇H₁₃N₂O₂, 335; found 335.

Example 56:2-[[4-(trifluoromethyl)phenyl]methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 80% yield using methyl2-[[4-(trifluoromethyl)-phenyl]methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.32 (s, 3H), 4.33 (s, 2H), 6.42 (s, 1H), 7.47 (d,J=5.05 Hz, 1H), 7.56 (d, J=8.08 Hz, 3H), 7.68 (d, J=8.08 Hz, 3H), 8.39(s, 1H), 11.38 (br. s., 1H), 13.67 (br. s., 1H). [M+H] calc'd forC₁₆H₁₁N₂O₂, 321; found 321.

Example 57: methyl2-(2-cyanoethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 5% yield using 4-cyano-1-butyneaccording to the procedure for the preparation of Example 4. ¹H NMR (400MHz, CDCl₃): δ ppm 2.84 (t, J=7.07 Hz, 2H) 3.28 (t, J=7.20 Hz, 2H) 4.06(s, 3H) 6.75 (s, 1H) 7.68 (d, J=5.31 Hz, 1H) 8.56 (d, J=5.05 Hz, 1H)9.58-9.87 (m, 1H). [M+H] calc'd for C₁₂H₁₁N₃O₂, 230; found 230.

Example 58: 2-(2-cyanoethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 71% yield using methyl2-(2-cyanoethyl)-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate according tothe procedure for the preparation of Example 5. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 2.98 (t, J=7.07 Hz, 2H) 3.18 (t, J=7.07 Hz, 2H)6.56-6.59 (m, 1H) 7.50 (d, J=4.80 Hz, 1H) 8.41 (d, J=4.80 Hz, 1H) 11.32(d, J=1.26 Hz, 1H) 13.71 (br. s., 1H). [M+H] calc'd for C₁₁H₉N₃O₂, 216;found 216.

Example 59:2-[(4-methoxyphenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

To a vial containing 1-[4-methoxy)phenyl]prop-2-yn-1-ol (1.62 g, 10.0mmol), Et₃SiH (1.91 mL, 12 mmol) in DCM (10 mL) at −78° C. was addedBF₃-Et₂O (1.48 mL, 12 mmol) dropwise. The reaction was capped andallowed to stir at −78° C. for 2 hr. The reaction was quenched withsaturated NH₄Cl and the aqueous layers were extracted with DCM. Thecombined organic layers were concentrated in vacuo and purified bycolumn chromatography (0-5% EtOAc/hexanes gradient, 12 g silica) toafford 1-methoxy-4-(prop-2-yn-1-yl)benzene (400 mg, 27%) as a clear oil.

The title compound was prepared in 4% yield using1-methoxy-4-(prop-2-yn-1-yl)benzene according to the procedure for thepreparation of Examples 4 and 5. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.72(s, 3H), 4.17 (s, 2H), 6.37 (s, 1H), 6.88 (d, J=8.08 Hz, 2H), 7.27 (d,J=8.34 Hz, 2H), 7.54 (br. s., 1H), 8.42 (br. s., 1H), 11.45-11.56 (m,1H). [M+H] calc'd for C₁₆H₁₄N₂O₃, 283; found 283.

Example 60:2-[(4-fluorophenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in <1% yield using1-fluoro-4-(prop-2-yn-1-yloxy)-benzene according to the procedure forthe preparation of Examples 9 and 5. ¹H NMR (400 MHz, CD₃OD): δ ppm 5.43(2H, s), 6.95 (1H, s), 7.05-7.079 (4H, m), 8.02 (1H, br), 8.64 (1H, br).LCMS (mobile phase: 0-60% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=2.416 min. [M+H] calc'd for C₁₅H₁₁FN₂O₃, 287; found 287.

Example 61:methyl-2-[(4-methylphenoxy)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in <1% yield using1-methyl-4-(prop-2-yn-1-yloxy)-benzene according to the procedure forthe preparation of Example 9. ¹H NMR (400 MHz, CD₃OD): δ ppm 2.17 (3H,s), 3.96 (3H, s), 5.21 (2H, s), 6.64 (1H, s), 6.84 (2H, d, J=8.8 Hz),7.00 (2H, d, J=8.4 Hz), 7.60 (1H, d, J=5.2 Hz), 8.32 (1H, d, J=4.8 Hz).[M+H] Calc'd for C₁₇H₁₆N₂O₃, 297; Found, 297.

Example 62:2-[(4-methylphenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 51% yield usingmethyl-2-[(4-methylphenoxy)-methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, CD₃OD): δ ppm 2.17 (3H, s), 5.33 (2H, s), 6.84-6.86 (3H, m), 7.02(2H, d, J=8.8 Hz), 7.94 (1H, d, J=6.4 Hz), 8.50 (1H, d, J=6.0 Hz). LCMS(mobile phase: 0-60% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%,Rt=4.234 min. [M+H] Calc'd for C₁₆H₁₄N₂O₃, 283; Found, 283.

Example 63:methyl-2-[(4-chlorophenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in <1% yield using1-chloro-4-(prop-2-yn-1-yloxy)-benzene according to the procedure forthe preparation of Example 9. ¹H NMR (400 MHz, CD₃OD): δ ppm 4.09 (3H,s), 5.37 (2H, s), 6.80 (1H, s), 7.07-7.09 (2H, s), 7.30-7.32 (2H, m),7.75 (1H, d, J=4.8 Hz), 8.47 (1H, d, J=5.2 Hz). [M+H] Calc'd forC₁₆H₁₃ClN₂O₃, 317; Found, 317.

Example 64:2-[(4-chlorophenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 75% yield usingmethyl-2-[(4-chlorophenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, CD₃OD): δ ppm 5.32 (2H, s), 6.79 (1H, s), 6.96 (2H, d, J=8.8 Hz),7.20 (2H, d, J=9.2 Hz), 7.84 (1H, d, J=5.6 Hz), 8.45 (1H, br). LCMS(mobile phase: 0-60% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%,Rt=4.345 min. [M+H] Calc'd for C₁₅H₁₁ClN₂O₃, 303; Found, 303.

Example 65: methyl2-[(2-methylphenoxy)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 2% yield using1-methyl-2-(prop-2-yn-1-yloxy)-benzene according to the procedure forthe preparation of Example 9. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.19 (3H,s), 3.99 (3H, s), 5.34 (2H, s), 6.77 (1H, s), 6.86-6.88 (1H, m), 7.08(1H, d, J=8.4 Hz), 7.16-7.18 (2H, m), 7.59 (1H, d, J=5.2 Hz), 8.48 (1H,d, J=4.8 Hz), 11.56 (1H, s). LCMS (mobile phase: 20-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.742 min. [M+H]calc'd for C₁₇H₁₆N₂O₃, 297; found 297.

Example 66:2-[(2-methylphenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 91% yield using methyl2-[(2-methylphenoxy)-methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 2.21 (3H, s), 5.41 (2H, s), 6.84-6.90 (2H, m), 7.05(1H, d, J=8.4 Hz), 7.17-7.20 (2H, m), 7.75 (1H, d, J=5.6 Hz), 8.59 (1H,d, J=5.2 Hz), 12.08 (1H, s). LCMS (mobile phase: 0-60%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=4.218 min. [M+H]Calc'd for C₁₆H₁₄N₂O₃, 283; Found, 283.

Example 67: methyl2-[[4-(trifluoromethyl)phenoxy]methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 2% yield using1-(prop-2-yn-1-yloxy)-4-trifluoro-methylbenzene according to theprocedure for the preparation of Example 9. ¹H NMR (400 MHz, DMSO-d₆): δppm 3.99 (3H, s), 5.43 (2H, s), 6.83 (1H, d, J=1.2 Hz), 7.27 (2H, d,J=8.4 Hz), 7.60 (1H, d, J=4.8 Hz), 7.70 (2H, d, J=8.8 Hz), 8.50 (1H, d,J=4.8 Hz), 11.63 (1H, s). LCMS (mobile phase: 20-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.876 min. [M+H]calc'd for C₁₇H₁₃N₂O₃F₃, 351; found 351.

Example 68:2-[[4-(trifluoromethyl)phenoxy]methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 85% yield using methyl2-[[4-(trifluoromethyl)-phenoxy]methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 5.43 (2H, s), 6.79 (1H, s), 7.25 (2H, d, J=8.8 Hz),7.58 (1H, d, J=4.8 Hz), 7.69 (2H, d, J=8.8 Hz), 8.48 (1H, d, J=4.0 Hz),11.62 (1H, s), 13.82 (1H, br). LCMS (mobile phase: 0-60%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=4.575 min. [M+H]calc'd for C₁₆H₁₁N₂O₃F₃, 337; found 337.

Example 69: methyl2-(2-phenylethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 33% yield using 4-phenyl-1-butyneaccording to the procedure for the preparation of Example 4. ¹H NMR (400MHz, CDCl₃): δ ppm 3.07-3.14 (m, 2H) 3.16-3.25 (m, 2H) 4.00 (s, 3H) 6.62(br. s., 1H) 7.21-7.25 (m, 2H) 7.28-7.39 (m, 3H) 7.59 (br. s., 1H) 8.49(br. s., 1H) 9.23 (br. s., 1H). [M+H] calc'd for C₁₇H₁₆N₂O₂, 281; found281.

Example 70: 2-(2-phenylethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 85% yield using methyl2-(2-phenylethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate according tothe procedure for the preparation of Example 5. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 3.00-3.08 (m, 2H) 3.11-3.20 (m, 2H) 6.41-6.45 (m, 1H)7.16-7.23 (m, 1H) 7.26-7.34 (m, 5H) 7.45 (d, J=5.05 Hz, 2H) 8.36 (d,J=5.05 Hz, 1H) 11.21 (br. s., 1H) 13.62 (br. s., 1H). [M+H] calc'd forC₁₆H₁₄N₂O₂, 267; found 267.

Example 71: (±)-methyl2-[(2-chlorophenyl)-hydroxymethyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 33% yield using(±)-1-(2-chlorophenyl)-prop-2-yn-1-ol according to the procedure for thepreparation of Example 4. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.04 (s, 3H),6.53 (s, 1H), 6.58-6.65 (m, 1H), 7.29-7.36 (m, 2H), 7.41 (d, J=2.02 Hz,1H), 7.61 (d, J=7.33 Hz, 1H), 7.64 (d, J=5.05 Hz, 1H), 8.51 (d, J=4.80Hz, 1H), 9.84 (br. s., 1H). [M+H] calc'd for C₁₆H₁₃N₂O₃Cl, 317; found317.

Example 72:(±)-2-[(2-chlorophenyl)-hydroxymethyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 88% yield using (±)-methyl2-[(2-chlorophenyl)-hydroxymethyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 6.12 (d, J=1.52 Hz, 1H), 6.30-6.40 (m, 2H),7.33-7.45 (m, 2H), 7.45-7.49 (m, 1H), 7.53 (d, J=4.80 Hz, 1H), 7.63 (dd,J=7.58, 1.77 Hz, 1H), 8.42 (d, J=5.05 Hz, 1H), 11.09 (br. s., 1H), 13.80(br. s., 1H). [M+H] calc'd for C₁₅H₁₁N₂O₃Cl, 303; found 303.

Example 73: methyl2-[(3-methylphenoxy)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in <1% yield using3-fluoro-4-(prop-2-yn-1-yloxy)-benzene according to the procedure forthe preparation of Example 9. ¹H NMR (400 MHz, DMSO-d₆): δ 2.19 (3H, s),3.99 (3H, s), 5.34 (2H, s), 6.77 (1H, s), 6.86-6.88 (1H, m), 7.08 (1H,d, J=8.4 Hz), 7.16-7.18 (2H, m), 7.59 (1H, d, J=5.2 Hz), 8.48 (1H, d,J=4.8 Hz), 11.56 (1H, s). LCMS (mobile phase: 20-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.491 min. [M+H]Calc'd for C₁₇H₁₆N₂O₃, 297; Found, 297.

Example 74:2-[(3-methylphenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 88% yield using methyl2-[(3-methylphenoxy)-methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 2.29 (3H, s), 5.36 (2H, s), 6.78-6.88 (4H, m),7.17-7.22 (1H, m), 7.73 (1H, d, J=7.2 Hz), 8.58 (1H, d, J=7.2 Hz), 12.02(1H, s). LCMS (mobile phase: 0-60% Acetonitrile-Water-0.02% NH₄Ac):purity is >95%, Rt=3.491 min. [M+H] Calc'd for C₁₆H₁₄N₂O₃, 283; Found,283.

Example 75:methyl-2-(2,3dihydro-1-benzofuran-5-yloxymethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

A mixture containing 2,3-dihydrobenzofuran-5-ol (3.12 mg, 23 mmol),3-bromo-propyne (3.3 g, 28 mmol), and K₂CO₃ (6.4 g, 46 mmol) in acetone(30 mL) was purged with nitrogen and stirred at 60° C. overnight. Thereaction was concentrated in vacuo and the residue suspended indichloromethane and filtered. The filtrate was concentrated in vacuo andthe residue purified by silica gel chromatograph (PE/EA=50/1-20/1) toafford 5-(prop-2-yn-1-yloxy)-2,3-dihydrobenzofuran (3.48 g, 86%) as ayellow oil.

The title compound was prepared in <1% yield using5-(prop-2-yn-1-yloxy)-2,3-dihydrobenzofuran according to the procedurefor the preparation of Example 9. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.15(2H, t, J=8.8 Hz), 3.99 (3H, s), 4.47 (2H, t, J=8.8 Hz), 5.24 (2H, s),6.67 (1H, d, J=8.4 Hz), 6.74-6.79 (2H, m), 6.98 (1H, d, J=2.8 Hz), 7.58(1H, d, J=4.8 Hz), 8.48 (1H, d, J=5.2 Hz), 11.53 (1H, s). LCMS (mobilephase: 20-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.105min. [M+H] Calc'd for C₁₈H₁₆N₂O₄, 325; Found, 325.

Example 76:2-(2,3dihydro-1-benzofuran-5-yloxymethyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 88% yield usingmethyl-2-(2,3dihydro-1-benzofuran-5-yloxymethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.15 (2H, t, J=8.4 Hz), 4.47 (2H, t, J=8.4 Hz),5.31 (2H, s), 6.68 (1H, d, J=8.4 Hz), 6.75-6.81 (2H, m), 6.98 (1H, d,J=2.4 Hz), 7.74 (1H, d, J=5.2 Hz), 8.59 (1H, d, J=5.6 Hz), 12.04 (1H,s). [M+H] Calc'd for C₁₇H₁₄N₂O₄, 311; Found, 311.

Example 77: methyl2-[(2-chlorophenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 74% yield using methyl2-[(2-chlorophenyl)-hydroxymethyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 34. ¹H NMR(400 MHz, CDCl₃): δ ppm 4.11 (s, 3H), 4.42 (s, 2H), 7.00 (s, 1H),7.28-7.38 (m, 3H), 7.45-7.51 (m, 1H), 7.89 (d, J=6.06 Hz, 1H), 8.62 (d,J=5.81 Hz, 1H), 10.14 (br. s., 1H). [M+H] Calc'd for C₁₆H₁₃ClN₂O₂, 301;Found, 301.

Example 78:2-[(2-chlorophenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 88% yield using methyl2-[(2-chlorophenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 4.28 (s, 2H), 6.14 (s, 1H), 7.22-7.33 (m, 3H),7.35-7.51 (m, 2H), 8.32 (d, J=5.05 Hz, 1H), 11.32 (br. s., 1H), 13.66(br. s., 1H). [M+H] Calc'd for C₁₅H₁₁ClN₂O₂, 287; Found, 287.

Example 79:2-[(3-fluorophenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in <1% yield using1-fluoro-3-(prop-2-yn-1-yloxy)-benzene according to the procedure forthe preparation of Examples 9 and 5. ¹H NMR (400 MHz, DMSO-d₆): δ ppm5.40 (2H, s), 6.79-6.84 (1H, m), 6.89-6.99 (3H, m), 7.33-7.39 (1H, m),7.76 (1H, d, J=4.8 Hz), 8.61 (1H, br), 12.11 (1H, s). LCMS (mobilephase: 5-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.321min. [M+H] Calc'd for C₁₅H₁₁FN₂O₃, 287; Found, 287.

Example 80:2-[(3-chlorophenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in <1% yield using1-chloro-3-(prop-2-yn-1-yloxy)-benzene according to the procedure forthe preparation of Examples 9 and 5. ¹H NMR (400 MHz, DMSO-d₆): δ ppm5.42 (2H, s), 6.90 (1H, s), 7.05 (2H, d, J=8.8 Hz), 7.18-7.19 (1H, m),7.35 (1H, t, J=8.4 Hz), 7.79 (1H, d, J=5.2 Hz), 8.61-8.63 (1H, m), 12.18(1H, s). LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac):purity is >95%, Rt=3.432 min. [M+H] Calc'd for C₁₅H₁₁ClN₂O₃, 303; Found,303.

Example 81:2-[(3,5-difluorophenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in <1% yield using1,3-difluoro-5-(prop-2-yn-1-yloxy)-benzene according to the procedurefor the preparation of Examples 9 and 5. ¹H NMR (400 MHz, DMSO-d₆): δppm 5.40 (2H, s), 6.82-6.90 (4H, m), 7.75 (1H, d, J=5.2 Hz), 8.60 (1H,d, J=5.2 Hz), 12.07 (1H, s). LCMS (mobile phase: 5-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.385 min. [M+H]Calc'd for C₁₅H₁₀F₂N₂O₃, 305; Found, 305.

Example 82:2-[(3,5-dimethylphenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in <1% yield using1,3-dimethyl-5-(prop-2-yn-1-yl-oxy)benzene according to the procedurefor the preparation of Examples 9 and 5. ¹H NMR (400 MHz, DMSO-d₆): δppm 2.24 (6H, s), 5.35 (2H, s), 6.62 (1H, s), 6.68 (2H, s), 8.83 (1H, d,J=2.0 Hz), 7.75 (1H, d, J=5.2 Hz), 8.59 (1H, d, J=5.6 Hz), 12.06 (1H,s). LCMS (mobile phase: 5-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=3.490 min. [M+H] Calc'd for C₁₆H₁₆N₂O₃, 297; Found, 297.

Example 83:2-[(3,5-dichlorophenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in <1% yield using1,3-dichloro-5-(prop-2-yn-1-yloxy)-benzene according to the procedurefor the preparation of Examples 9 and 5. ¹H NMR (400 MHz, DMSO-d₆): δppm 5.37 (2H, s), 6.79 (1H, s), 7.19 (3H, s), 7.59 (1H, s), 8.59 (1H, s,br), 11.59 (1H, s), 13.80 (1H, s). LCMS (mobile phase: 5-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.490 min. [M+H]Calc'd for C₁₅H₁₀Cl₂N₂O₃, 337; Found, 337.

Example 84:(±)-2-(1-phenoxyethyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

To a mixture containing (±)-3-butyn-2-ol (2.02 g, 29 mmol), TsCl (6.8 g,36 mmol) in Et₂O (30 mL) was added KOH (10.0 g, 174 mmol) at 0° C. Themixture was stirred at 0° C. for 1.5 hr and filtered. The filtrate wasconcentrated in vacuo to afford(±)-(but-3-yn-2-yl)-4-methylphenylsulfonate (2.03 g, 31%) as a yellowoil. ¹H NMR (400 MHz, CDCl₃): δ ppm 1.57 (3H, d, J=6.8 Hz), 2.41-2.42(1H, m), 2.45 (3H, s), 5.14-4.19 (1H, m), 7.34 (2H, d, J=8.0 Hz), 7.82(2H, d, J=8.4 Hz).

To a mixture containing phenol (1.0 g, 10 mmol) and KOH (0.6 g, 10 mmol)in 95% EtOH (20 mL) was added(±)-(but-3-yn-2-yl)-4-methylphenylsulfonate (2.0 g, 9 mmol) at 0° C. Themixture was heated at 65° C. overnight. H₂O was added and the mixturewas extracted with Et₂₀. The organic layers were concentrated andpurified by silica gel chromatography (PE/EA=10/1) to afford(±)-(but-3-yn-2-yloxy)benzene (690 mg, 50%). ¹H NMR (400 MHz, CDCl₃): δppm 1.66 (3H, d, J=6.4 Hz), 2.46 (1H, d, J=1.6 Hz), 4.85-4.90 (1H, m),6.96-7.02 (3H, m), 7.25-7.32 (2H, m).

The title compound was prepared in 10% yield using(±)-(but-3-yn-2-yloxy)benzene according to the procedure for thepreparation of Examples 9 and 5. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.69(3H, d, J=6.4 Hz), 5.84-5.89 (1H, m), 6.59 (1H, s), 6.87-6.97 (3H, m),7.21-7.26 (2H, m), 7.54 (1H, d, J=4.8 Hz), 8.41-8.45 (1H, m), 11.48 (1H,s), 13.85 (1H, bs). LCMS (mobile phase: 5-95% Acetonitrile-Water-0.02%NH₄Ac): purity is >95%, Rt=3.266 min.

Example 85:(±)-2-(1-phenoxybutyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in <1% yield using (±)-1-hexyn-3-olaccording to the procedure for the preparation of Example 84. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.94 (3H, t, J=6.4 Hz), 1.38-1.54 (2H, m),1.93-2.05 (2H, m), 5.71-5.74 (1H, m), 6.54 (1H, s), 6.85-6.96 (3H, m),7.20-7.24 (2H, m), 7.53 (1H, s), 8.48-8.52 (1H, m), 11.45 (1H, s), 13.80(1H, bs). LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac):purity is >95%, Rt=3.597 min. [M+H] Calc'd for C₁₈H₁₈N₂O₃, 311; Found,311.

Example 86:(±)-2-(3-methyl-phenoxybutyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in <1% yield starting from(±)-5-methlyl-1-hexyn-3-ol according to the procedure for thepreparation of Example 84. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.95-0.99(6H, m), 1.76-1.86 (2H, m), 1.97-2.052 (1H, m), 5.78-5.81 (1H, m), 6.57(1H, s), 6.85-6.88 (1H, m), 6.97 (2H, d, J=8.0 Hz), 7.20-7.24 (2H, m),7.52 (1H, d, J=4.0 Hz), 8.39-8.43 (1H, m). LCMS (mobile phase: 5-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.679 min. [M+H]Calc'd for C₁₉H₂₀N₂O₃, 325; Found, 325.

Example 87: (1)-methyl2-[(2-chlorophenyl)propoxymethyl])-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

To a round-bottom flask charged with(±)-1-(2-chloro-phenyl)-prop-2-yn-1-ol (1.165 g, 7 mmol) in DMF wasadded NaH (336 mg, 8.4 mmol, 60% mineral oil suspension) portion-wise.The reaction was stirred for 30 min at ambient temp under N₂ atmosphere.1-bromopropane was added dropwise at 0° C. and the reaction was allowedto warm to ambient temperature and stirred for 16 hr. The reaction wasquenched with saturated NH₄Cl and extracted with EtOAc (2×). Thecombined organic layers were successively washed with water (2×),followed by brine, dried with Na₂SO₄ and concentrated in vacuo. Theresidue purified by silica gel chromatography (0%-5% gradient of EtOAcin hexanes) to afford (±)-1-(2-chlorophenyl)prop-2-yn-1-yl propyl ether(1.2 g, 82%) as a light yellow oil.

The title compound was prepared in 15% yield using(±)-1-(2-chlorophenyl)prop-2-yn-1-yl propyl ether according to theprocedure for the preparation of Example 4. ¹H NMR (400 MHz, CDCl₃): δppm 1.00 (t, J=7.45 Hz, 3H), 1.72 (dq, J=14.02, 6.95 Hz, 2H), 3.55 (t,J=6.57 Hz, 2H), 3.87-4.62 (m, 4H), 4.03 (s, 3H), 6.10 (s, 1H), 6.60 (br.s., 1H), 7.28-7.50 (m, 3H), 7.52-7.75 (m, 2H), 8.51 (br. s., 1H), 9.71(br. s., 1H). [M+H] Calc'd for C₁₉H₁₉ClN₂O₃, 359; Found, 359.

Example 88:(±)-2-[(2-chlorophenyl)propoxymethyl])-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 15% yield using (±)-methyl2-[(2-chlorophenyl)-propoxymethyl])-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation of Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.90 (t, J=7.33 Hz, 3H) 1.60 (m, 2H) 3.40-3.52 (m,2H) 3.40-3.52 (m, 2H) 3.54-3.64 (m, 1H) 6.11-6.14 (m, 1H) 6.24 (d,J=2.02 Hz, 1H) 6.55-6.59 (m, 1H) 7.35-7.45 (m, 2H) 7.47-7.52 (m, 2H)7.54 (d, J=5.05 Hz, 1H) 8.44 (d, J=4.80 Hz, 1H) 11.33 (br. s., 1H) 13.76(br. s., 1H). [M+H] Calc'd for C₁₈H₁₇ClN₂O₃, 345; Found, 345.

Example 89: methyl2-[(2,4-dichlorophenyl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 10% yield using2,4-dichloro-1-(prop-2-yn-1-yl)-benzene according to the procedure forthe preparation of Example 55. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.02 (s,3H), 4.31 (s, 2H), 6.61 (s, 1H), 7.20-7.23 (m, 1H), 7.46 (d, J=1.77 Hz,1H), 7.61 (d, J=5.05 Hz, 1H), 8.51 (d, J=5.31 Hz, 1H), 9.54 (br. s.,1H). [M+H] Calc'd for C₁₆H₁₂Cl₂N₂O₂, 335; Found, 335.

Example 90:2-[(2,4-dichlorophenyl)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 88% yield using5-methlyl-1-hexyn-3-ol according to the procedure for the preparation ofExample 5. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.33 (s, 2H) 6.24 (s, 1H)7.31-7.44 (m, 2H) 7.49 (d, J=5.31 Hz, 1H) 7.66 (s, 1H) 8.39 (d, J=4.55Hz, 1H) 11.43 (br. s., 1H) 13.70 (br. s., 1H). [M+H] Calc'd forC₁₅H₁₀Cl₂N₂O₂, 321; Found, 321.

Example 91: methyl2-(1-benzofuran-2-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

A mixture containing methyl 3-amino-2-chloroisonicotinate (372 mg, 2mmol), 2-benzofuranyl methyl ketone (960 mg, 6 mmol), MgSO₄ (120 mg, 1mmol), and AcOH (150 μL, 3 mmol) in DMA was purged with N₂ for 10 min.Pd(tBu₃P)₂ (101 mg, 0.2 mmol) and K₃PO₄ (552 mg, 2.6 mmol) were addedand the reaction sealed and heated at 140° C. for 16 hr. The reactionmixture was taken up in EtOAc and washed successively with water (2×),brine, and dried with N₂SO₄. The organic layers were concentrated invacuo and the residue purified by column chromatography to afford thetitle compound (152 mg, 26%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.33 (s, 2H), 6.24 (s, 1H), 7.31-7.44 (m, 2H), 7.49 (d,J=5.31 Hz, 1H), 7.66 (s, 1H), 8.39 (d, J=4.55 Hz, 1H), 11.43 (br. s.,1H), 13.70 (br. s., 1H). [M+H] Calc'd for C₁₇H₁₂N₂O₃, 293; Found, 293.

Example 92: 2-(1-benzofuran-2-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 75% yield using5-methlyl-1-hexyn-3-ol according to the procedure for the preparation ofExample 5. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.21 (s, 1H) 7.32 (d, J=7.58Hz, 1H) 7.39 (s, 1H) 7.62 (d, J=4.80 Hz, 1H) 7.69 (d, J=8.08 Hz, 1H)7.74 (d, J=7.58 Hz, 1H) 7.95 (s, 1H) 8.54 (d, J=5.05 Hz, 1H) 11.55 (br.s., 1H) 13.88 (br. s., 1H).

Example 93:2-[(4-methoxyphenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in <1% yield using1-methoxy-4-(prop-2-yn-1-yloxy)-benzene according to the procedure forthe preparation of Examples 9 and 5. ¹H NMR (400 MHz, DMSO-d₆): δ ppm3.69 (3H, s), 5.27 (2H, s), 6.72 (1H, s), 6.87-6.90 (2H, m), 6.97-7.00(2H, m), 7.56-7.57 (1H, m), 8.47-8.53 (1H, m), 11.53 (1H, s), 13.78 (1H,br s). LCMS (mobile phase: 5-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=3.137 min. [M+H] Calc'd for C₁₆H₁₄N₂O₄, 299; Found, 299.

Example 94:2-[(2-chlorophenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in <1% yield using2-chloro-(prop-2-yn-1-yloxy)benzene according to the procedure for thepreparation of Examples 9 and 5. ¹H NMR (400 MHz, CD₃OD): δ ppm 5.41(2H, s), 6.84 (1H, s), 6.88-6.91 (1H, m), 7.11-7.13 (1H, m), 7.17-7.21(1H, m), 7.31-7.33 (1H, m), 7.85 (1H, br s), 8.46 (1H, br s). LCMS(mobile phase: 5-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%,Rt=3.372 min. [M+H] Calc'd for C₁₅H₁₁ClN₂O₃, 303; Found: 303.

Example 95:2-[(2-fluorophenox)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in <1% yield using2-fluoro-(prop-2-yn-1-yloxy)-benzene according to the procedure for thepreparation of Examples 9 and 5. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 5.40(2H, s), 6.78 (1H, s), 6.94-6.99 (1H, m), 7.14-7.21 (1H, m), 7.24-7.31(1H, m), 7.33-7.35 (1H, m), 7.58-7.59 (1H, m), 8.47-8.49 (1H, m), 11.61(1H, br), 13.61 (1H, br). LCMS (mobile phase: 5-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.300 min. [M+H]Calc'd for C₁₅H₁₁FN₂O₃, 287; Found, 287.

Example 96:2-[(2-chloro-4-fluorophenoxy)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in <1% yield using2-chloro-4-fluoro-(prop-2-yn-1-yl-oxy)benzene according to the procedurefor the preparation of Examples 9 and 5. ¹H NMR (400 MHz, DMSO-d₆): δppm 5.39 (2H, s), 6.83 (1H, s), 6.94-6.99 (1H, m), 7.11-7.19 (2H, m),7.84-7.86 (1H, m), 8.46 (1H, br). LCMS (mobile phase: 5-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.633 min. [M+H]Calc'd for C₁₅H₁₀ClFN₂O₃, 321; Found, 321.

Example 97:2-{[4-(acetylamino)phenoxy]methyl}-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in <1% yield usingN-[4-(prop-2-yn-1-yl)phenyl]-acetamide according to the procedure forthe preparation of Examples 9 and 5. ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.76 (3H, s), 5.32 (2H, s), 6.81 (1H, bs), 6.79 (1H, s), 6.82-6.85 (3H,m), 7.14 (1H, s), 7.28 (1H, d, J=10.0 Hz), 7.73-7.77 (2H, m), 7.81 (1H,br), 9.83 (1H, s), 11.96 (1H, br). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.758 min. [M+H]Calc'd for C₁₇H₁₅N₃O₄, 326; Found, 326.

Example 98:2-[(4-cyanophenoxy)methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in <1% yield using4-(prop-2-yn-1-yl)benzo-nitrile according to the procedure for thepreparation of Examples 9 and 5. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 5.42(2H, s), 6.79 (1H, s), 7.24 (2H, d, J=9.2 Hz), 7.57-7.59 (1H, m), 7.83(2H, d, J=6.8 Hz), 8.48 (1H, d, J=5.2 Hz), 11.62 (1H, s), 13.79 (1H,br). LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=2.432 min. [M+H] Calc'd for C₁₆H₁₁N₃O₃, 294; Found, 294.

Example 99:2-(pyrrolidin-1-ylcarbonyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

To a round-bottom flask charged with pyruvic acid (693 μL, 10 mmol), DMF(2 drops) in DCM (10 mL) was added SOCl₂ (730 μL, 20 mmol) dropwise at0° C. The reaction was stirred at ambient temp for 30 min. Pyrrollidine(2.5 mL, 30 mmol) was added dropwise at 0° C. The reaction was allowedto stir for 1 hr at ambient temp. The reaction was taken up in DCM andthe organic layers were successively washed with water, brine, driedwith Na₂SO₄, and concentrated in vacuo. The residue was purified bycolumn chromatography (0-30% gradient of EtOAc in Hexanes) to afford1-(pyrrolidin-1-yl)propane-1,2-dione (335 mg, 24%).

The title compound was prepared in 34% yield using1-(pyrrolidin-1-yl)propane-1,2-dione according to the procedure for thepreparation of Example 91, except the product was purified by prep-HPLC(10-95% ACN/water, 0.1% HCO₂H). ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.72-2.16 (m, 5H), 3.58 (t, J=6.82 Hz, 2H), 3.85 (t, J=6.69 Hz, 2H),7.11-7.38 (m, 1H), 7.69 (d, J=4.80 Hz, 1H), 8.61 (d, J=4.80 Hz, 1H),10.30-10.54 (m, 1H), 13.90-14.19 (m, 1H). [M+H] Calc'd for C₁₃H₁₃N₃O₃,260; Found, 260.

Example 100: methyl2-[(4-fluorophenyl)methyl]pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in <1% yield starting with4-fluorobenzaldehyde according to the procedure for the preparation ofExample 55 and 9. ¹H NMR (400 MHz, CDCl₃): δ ppm 3.99 (3H, s), 4.17 (2H,s), 6.58 (1H, s), 7.03 (2H, t, J=8.4 Hz), 7.22-7.25 (2H, m), 7.56 (1H,d, J=4.0 Hz), 8.51-8.53 (1H, m), 9.24 (1H, bs). LCMS (mobile phase:10%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.573 min.[M+H] Calc'd for C₁₆H₁₃FN₂O₂, 285; Found, 285.

Example 101:2-[(4-fluorophenyl)methyl]pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 61% yield using methyl2-[(4-fluorophenyl)-methyl]pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 4.05 (2H, s), 6.36 (1H, s), 7.12-7.18 (2H, m),7.36-7.51 (2H, m), 8.38 (1H, m), 11.33 (1H, s), 13.69 (1H, bs). LCMS(mobile phase: 5-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%,Rt=3.250 min. [M+H] Calc'd for C₁₅H₁₁FN₂O₂, 271; Found, 271.

Example 102: methyl2-[1-(4-fluorophenyl)-1-hydroxyethyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 15% yield using2-(4-fluorophenyl)-3-butyn-2-ol according to the procedure for thepreparation of Example 4. ¹H NMR (400 MHz, CDCl₃-d): δ ppm 2.08 (s, 3H),4.02 (s, 3H), 6.81 (br. s., 1H), 7.03 (t, J=8.72 Hz, 2H), 7.46 (dd,J=8.72, 5.18 Hz, 2H), 7.68 (br. s., 1H), 8.52 (d, J=4.80 Hz, 1H), 9.73(br. s., 1H). [M+H] Calc'd for C₁₇H₁₅FN₂O₃, 315; Found, 315.

Example 103:2-[1-(4-fluorophenyl)-1-hydroxyethyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 86% yield using methyl2-[1-(4-fluorophenyl)-1-hydroxyethyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.89 (s, 3H), 6.41 (s, 1H), 6.67 (s, 1H), 7.14 (t,J=8.84 Hz, 2H), 7.45 (dd, J=8.84, 5.56 Hz, 2H), 7.51 (d, J=5.05 Hz, 1H),8.45 (d, J=4.80 Hz, 1H), 10.29 (br. s., 1H), 13.81 (br. s., 1H). [M+H]Calc'd for C₁₆H₁₃FN₂O₃: 301; Found: 301.

Example 104: methyl2-(1,2,3,4-tetrahydroquinolylcarbonyl)pyrrolo[3,2-b]-pyridine-7-carboxylate

To a round-bottom flask charged with pyruvic acid (1.39 mL, 20 mmol),DMF (2 drops) in DCM (40 mL) was added SOCl₂ (1.46 mL, 20 mmol) dropwiseat 0° C. The reaction was stirred at ambient temp for 30 min. DIEA (7.2mL, 40 mmol) was added slowly at 0° C. followed by dropwise addition of1,2,3,4-tetrahydroquinoline (2.66 g, 20 mmol). The reaction was allowedto stir for 1 hr at ambient temp. The reaction was taken up in DCM andthe organic layers were successively washed with water, brine, driedwith Na₂SO₄, and concentrated in vacuo. The residue was purified bycolumn chromatography (0%-30% gradient of EtOAc in Hexanes) to afford1-(3.4-dihydroquinolin-1-(2H)-yl)propane-1,2-dinone (480 mg, 30%).

The title compound was prepared in 10% yield using1-(3.4-dihydroquinolin-1-(2H)-yl)-propane-1,2-dinone according to theprocedure for the preparation of Example 91, except the product waspurified by prep-HPLC (20-80% ACN/water, 0.1% NH₄Ac). ¹H NMR (400 MHz,CDCl₃): δ ppm 2.06-2.13 (2H, m), 2.83-2.86 (2H, m), 4.01-4.05 (2H, m),4.07 (3H, s), 6.44 (1H, s), 7.02-7.26 (3H, m), 7.26-7.27 (1H, m), 7.78(1H, d, J=4.4 Hz), 8.59 (1H, d, J=4.8 Hz), 10.02 (1H, bs). LCMS (mobilephase: 20%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.363min. [M+H] Calc'd for C₁₉H₁₇N₃O₃, 336; Found, 336.

Example 105:2-(1,2,3,4-tetrahydroquinolylcarbonyl)pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 65% yield methyl2-(1,2,3,4-tetrahydroquinolyl-carbonyl)pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.95-2.01 (2H, m), 2.81-2.85 (2H, m), 3.84-3.88(2H, m), 6.52 (1H, s), 6.97-7.10 (2H, m), 7.19-7.28 (2H, m), 7.63 (1H,d, J=4.4 Hz), 8.52 (1H, d, J=4.8 Hz), 11.11 (1H, bs), 13.93 (1H, bs).LCMS (mobile phase: 20%-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=3.148 min. [M+H] Calc'd for C₁₈H₁₅N₃O₃, 322; Found, 322.

Example 106: methyl2-(indolinylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 2% yield starting with indolineaccording to the procedure for the preparation of Example 104. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 3.21-3.25 (2H, m), 4.01 (3H, s), 4.42-4.46(2H, m), 7.09-7.13 (1H, m), 7.23-7.35 (2H, m), 7.74 (1H, d, J=4.4 Hz),8.21-8.23 (1H, m), 8.64 (1H, d, J=4.8 Hz), 11.11 (1H, s). LCMS (mobilephase: 10%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.741min. [M+H] Calc'd for C₁₈H₁₅N₃O₃, 322; Found, 322.

Example 107: 2-(indolinylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 40% yield methyl2-(indolinylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylate according tothe procedure for the preparation in Example 5. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 3.21-3.27 (2H, m), 4.48-4.51 (2H, m), 7.09-7.14 (1H, m),7.25-7.29 (3H, m), 7.71 (1H, d, J=4.4 Hz), 8.16-8.23 (1H, m), 8.64 (1H,d, J=4.8 Hz), 10.80 (1H, s). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.365 min. [M+H]Calc'd for C₁₇H₁₃N₃O₃, 308; Found, 308.

Example 108: methyl2-(piperidylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 4% yield starting with piperidineaccording to the procedure for the preparation of Example 104. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.57-1.65 (6H, m), 3.53-3.64 (4H, m), 3.99(3H, s), 6.89 (1H, s), 7.66 (1H, d, J=4.8 Hz), 8.57 (1H, d, J=4.8 Hz),11.47 (1H, s). LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.02%NH₄Ac): purity is >95%, Rt=3.050 min. [M+H] Calc'd for C₁₅H₁₇N₃O₃, 288;Found, 288.

Example 109: 2-(piperidylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 25% yield methyl2-(piperidylcarbonyl)pyrrolo-[3,2-b]pyridine-7-carboxylate according tothe procedure for the preparation in Example 5. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.54-1.64 (6H, m), 3.46-3.63 (4H, m), 6.99 (1H, s), 7.80(1H, d, J=5.2 Hz), 8.66 (1H, d, J=4.4 Hz), 11.85 (1H, s). LCMS (mobilephase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.208min. [M+H] Calc'd for C₁₄H₁₅N₃O₃, 274; Found, 274.

Example 110:2-[1-(4-fluorophenyl)ethyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

To a vial containing methyl2-[1-(4-fluorophenyl)-1-hydroxyethyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate(31.4 mg, 0.1 mmol), and Et₃SiH (79 μL, 0.5 mmol) was added TFA (76 μL,1 mmol). The reaction was stirred at ambient temp for 16 hr andconcentrated in vacuo. The residue was taken up in MeOH (5 mL) followedby addition of Pd—C (50 mg, 10%), and kept under 1 ATM of H₂ at ambienttemperature for 2 hrs. The suspension was filtered through a pad ofcelite and concentrated in vacuo. The residue was converted to titlecompound in 46% yield according to the procedure for the preparation inExample 5. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.64 (d, J=7.07 Hz, 3H),4.49-4.62 (m, 1H), 6.55 (s, 1H), 7.12 (t, J=8.72 Hz, 2H), 7.36 (dd,J=8.59, 5.56 Hz, 2H), 7.46 (d, J=5.56 Hz, 1H), 8.38 (d, J=4.80 Hz, 1H),11.03-11.15 (m, 1H). [M+H] Calc'd for C₁₆H₁₃FN₂O₂, 275; Found, 275.

Example 111:methyl-2-(3-chloro-4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 4% yield starting with3-chloro-4-fluorobenzaldehyde according to the procedure for thepreparation of Example 55. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.00 (s, 3H),4.18 (s, 2H), 6.56-6.63 (m, 1H), 7.11-7.31 (m, 2H), 7.29-7.31 (m, 2H),7.61 (d, J=4.70 Hz, 1H), 8.53 (s, 1H), 9.35 (br. s., 1H). [M+H] Calc'dfor C₁₆H₁₂ClFN₂O₂, 319; Found, 319.

Example 112:2-(3-chloro-4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 78% yield usingmethyl-2-(3-chloro-4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.26-3.36 (m, 3H), 4.19-4.26 (m, 2H), 6.42 (s, 1H),7.32-7.41 (m, 2H), 7.47 (d, J=4.80 Hz, 1H), 7.59 (d, J=7.83 Hz, 1H),8.38 (d, J=5.05 Hz, 1H), 11.35 (br. s., 1H), 13.67 (br. s., 1H). [M+H]Calc'd for C₁₅H₁₀ClFN₂O₂, 305; Found, 305.

Example 113: methyl2-(4-chloro-3-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 11% yield starting with4-chloro-3-fluorobenzaldehyde according to the procedure for thepreparation of Example 55. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.00 (s, 3H),4.19 (s, 2H), 6.56-6.63 (m, 1H), 6.92-7.11 (m, 2H), 7.36 (t, J=7.83 Hz,1H), 7.58 (d, J=4.80 Hz, 1H), 8.53 (d, J=5.05 Hz, 1H), 9.30 (br. s.,1H). [M+H] Calc'd for C₁₆H₁₂ClFN₂O₂, 319; Found, 319.

Example 114:2-(4-chloro-3-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 72% yield using methyl2-(4-chloro-3-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 4.24 (s, 2H), 6.43 (d, J=2.02 Hz, 1H), 7.19-7.27(m, 1H), 7.42 (dd, J=10.48, 1.89 Hz, 1H), 7.47 (d, J=4.80 Hz, 1H), 7.52(t, J=8.08 Hz, 1H), 8.39 (d, J=5.05 Hz, 1H), 11.35 (br. s., 1H), 13.67(br. s., 1H). [M+H] Calc'd for C₁₅H₁₀ClFN₂O₂, 305; Found, 305.

Example 115: methyl2-[(3-phenylpyrrolidinyl)carbonyl]pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 20% yield starting with3-phenylpyrrolidine according to the procedure for the preparation ofExample 104. ¹H NMR (400 MHz, CDCl₃): δ ppm 2.15-2.27 (1H, m), 2.41-2.56(1H, m), 3.49-3.61 (1H, m), 3.74-3.89 (2H, m), 4.01-4.07 (4H, m),4.17-4.44 (1H, m), 7.16 (1H, d, J=16.8 Hz), 7.28-7.35 (3H, m), 7.36-7.39(2H, m), 7.77-7.80 (1H, m), 8.64-8.67 (1H, m), 10.56 (1H, s). LCMS(mobile phase: 10%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%,Rt=3.782 min. [M+H] Calc'd for C₂₀H₁₉N₃O₃, 350; Found, 350.

Example 116:2-[(3-phenylpyrrolidinyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 82% yield methyl2-[(3-phenylpyrrolidinyl)-carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 2.05-2.17 (1H, m), 2.31-2.47 (1H, m), 3.46-3.57(1.5H, m), 3.63-3.66 (0.5H, m), 3.83-3.88 (1H, m), 3.95-4.02 (0.5H, m),4.07-4.12 (1H, m), 4.31-4.36 (0.5H, m), 7.24-7.40 (6H, m), 7.68-7.71(1H, m), 8.60-8.64 (1H, m), 10.45-10.49 (1H, m), 14.12 (1H, br). LCMS(mobile phase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%,Rt=2.671 min. [M+H] Calc'd for C₁₈H₁₇N₃O₃, 336; Found, 336.

Example 117: methyl2-[(4,4-dimethylpiperidyl)carbonyl]pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 21% yield starting with4,4-dimethylpiperidine according to the procedure for the preparation ofExample 104. ¹H NMR (300 MHz, CDCl₃): δ ppm 1.07 (6H, s), 1.47-1.51 (4H,m), 3.78-3.93 (4H, m), 4.06 (3H, s), 7.01 (1H, s), 7.77 (1H, d, J=4.8Hz), 8.65 (1H, d, J=4.8 Hz), 10.03 (1H, bs). LCMS (mobile phase: 10%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.407 min. [M+H]Calc'd for C₁₇H₂₁N₃O₃, 316; Found, 316.

Example 118:2-[(4,4-dimethylpiperidyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 70% yield methyl2-[(4,4-dimethylpiperidyl)-carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.54-1.64 (6H, m), 3.46-3.63 (4H, m), 6.99 (1H, s),7.80 (1H, d, J=5.2 Hz), 8.66 (1H, d, J=4.4 Hz), 11.85 (1H, s). LCMS(mobile phase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%,Rt=2.208 min. [M+H] Calc'd for C₁₄H₁₅N₃O₃, 274; Found, 274.

Example 119: methyl2-[(3-phenylpiperidyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 12% yield starting with3-phenylpiperidine according to the procedure for the preparation ofExample 104. ¹H NMR (400 MHz, CDCl₃): δ ppm 1.69-1.83 (3H, m), 1.86-1.99(1H, m), 2.81-2.85 (2H, m), 2.89-2.94 (1H, m), 3.96-3.99 (4H, m),4.57-4.60 (1H, m), 6.95 (1H, s), 7.17-7.35 (5H, m), 7.66-7.67 (1H, m),7.78 (1H, d, J=4.4 Hz), 8.57 (1H, br), 11.58 (1H, bs). LCMS (mobilephase: 20%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.323min. [M+H] Calc'd for C₂₁H₂₁N₃O₃, 364; Found, 364.

Example 120:2-[(3-phenylpiperidyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 50% yield methyl2-[(3-phenylpiperidyl)carbonyl]-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.55-2.05 (5H, m), 2.75-3.02 (2H, m), 3.32-3.38(2H, m), 6.91 (1H, bs), 7.18-7.45 (5H, m), 7.68-7.72 (1H, m), 8.65 (1H,br), 11.88 (1H, bs). LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.02%NH₄Ac): purity is >95%, Rt=2.619 min. [M+H] Calc'd for C₂₀H₁₉N₃O₃, 350;Found, 350.

Example 121: methyl2-(2-1,2,3,4-tetrahydroisoquinolylcarbonyl)pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 35% yield starting with1,2,3,4-tetrahydroisoquinoline according to the procedure for thepreparation of Example 104. ¹H NMR (400 MHz, CD₃OD): δ ppm 2.88-2.91(2H, m), 3.86-3.89 (2H, m), 3.94 (3H, s), 4.88 (2H, br), 6.96-7.09 (5H,m), 7.70 (1H, d, J=4.8 Hz), 8.46 (1H, d, J=4.4 Hz). LCMS (mobile phase:10%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.468 min.[M+H] Calc'd for C₁₉H₁₇N₃O₃, 336; Found, 336.

Example 122:2-(2-1,2,3,4-tetrahydroisoquinolylcarbonyl)pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 65% yield methyl methyl2-(2-1,2,3,4-tetrahydro-isoquinolylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ 2.93-2.95 (2H, m), 3.85-3.88 (2H, m), 4.82-4.89 (2H,m), 7.09-7.30 (5H, m), 7.70 (1H, d, J=4.8 Hz), 8.61 (1H, d, J=4.8 Hz),11.26-11.28 (1H, br). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.468 min. [M+H]Calc'd for C₁₈H₁₅N₃O₃, 322; Found, 322.

Example 123: methyl2-[(2,2-dimethylpyrrolidinyl)carbonyl]pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 35% yield starting with2,2-dimethylpyrrolidine according to the procedure for the preparationof Example 104. ¹H NMR (300 MHz, CDCl₃): δ ppm 1.62 (6H, s), 1.80-1.95(2H, m), 1.99-2.06 (2H, m), 3.98-4.02 (2H, m), 4.06 (3H, s), 7.09 (1H,d, J=2.4 Hz), 7.78 (1H, d, J=4.8 Hz), 8.64 (1H, d, J=4.8 Hz), 10.22 (1H,bs). LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=3.404 min. [M+H] Calc'd for C₁₆H₁₉N₃O₃, 302; Found, 302.

Example 124:2-[(2,2-dimethylpyrrolidinyl)carbonyl]pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 50% yield methyl2-[(2,2-dimethylpyrrolidinyl)-carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (300MHz, DMSO-d₆): δ ppm 1.52 (6H, s), 1.83-1.92 (4H, m), 3.83-3.86 (2H, m),7.15 (1H, s), 7.72 (1H, d, J=4.8 Hz), 8.62 (1H, d, J=4.8 Hz), 10.73 (1H,bs). LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=2.296 min. [M+H] Calc'd for C₁₅H₁₇N₃O₃, 288; Found, 288.

Example 125: methyl2-(3,4-difluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in 17% yield starting with3,4-difluorobenzaldehyde according to the procedure for the preparationof Example 55. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.00 (s, 3H), 4.18 (s,2H), 6.55-6.65 (m, 1H), 6.94-7.18 (m, 3H), 7.58 (d, J=5.05 Hz, 1H), 8.53(d, J=5.05 Hz, 1H), 9.31 (br. s., 1H). [M+H] Calc'd for C₁₆H₁₂F₂N₂O₂,303; Found, 303.

Example 126:2-(3,4-difluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 87% yield using methyl2-(3-difluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate accordingto the procedure for the preparation in Example 5. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 4.22 (s, 2H), 6.33-6.46 (m, 1H), 7.20 (br. s., 1H),7.31-7.45 (m, 2H), 7.47 (d, J=4.80 Hz, 1H), 8.38 (d, J=5.05 Hz, 1H),11.34 (br. s., 1H),13.67 (br. s., 1H). [M+H] Calc'd for C₁₅H₁₀F₂N₂O₂,289; Found, 289.

Example 127: methyl2-(4-chloro-3-methoxybenzyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in <1% yield starting with3-methoxy-4-chlorobenzaldehyde according to the procedure for thepreparation of Example 59. ¹H NMR (400 MHz, CDCl₃): δ ppm 3.87 (s, 3H),4.04 (s, 3H), 4.23 (s, 2H), 6.76-6.90 (m, 2H), 7.35 (d, J=8.08 Hz, 2H),7.64-7.78 (m, 1H), 8.51 (d, J=5.56 Hz, 1H), 9.45-9.62 (m, 1H). [M+H]Calc'd for C₁₇H₁₅ClN₂O₃: 331; Found: 331.

Example 128:2-(4-chloro-3-methoxybenzyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 12% yield using methyl2-(4-chloro-3-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, CD₃OD): δ ppm 3.80-3.92 (m, 3H), 4.31 (s, 2H), 6.43-6.50 (m, 1H),6.82-6.95 (m, 1H), 7.03-7.14 (m, 1H), 7.25-7.39 (m, 1H), 7.73-7.82 (m,1H), 8.34-8.46 (m, 1H). [M+H] Calc'd for C₁₆H₁₃ClN₂O₃, 317; Found, 317.

Example 129: methyl2-(3,4-dichlorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

The title compound was prepared in <5% yield starting with3,4-dichlorobenzaldehyde according to the procedure for the preparationof Example 55. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.02 (s, 3H), 4.19 (s,2H), 6.62-6.79 (m, 1H), 7.11 (d, J=10.11 Hz, 1H), 7.36 (m, 1H), 7.42 (d,J=8.08 Hz, 1H), 7.60-7.68 (m, 1H), 8.48-8.59 (m, 1H), 9.31-9.46 (m, 1H).[M+H] Calc'd for C₁₆H₁₂Cl₂N₂O₂, 335; Found, 335.

Example 130:2-(3,4-dichlorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 70% yield using methyl2-(3,4-dichlorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate accordingto the procedure for the preparation in Example 5. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 4.23 (s, 2H), 6.45 (d, J=2.02 Hz, 1H), 7.32-7.38 (m,1H), 7.48 (d, J=4.80 Hz, 1H), 7.57 (d, J=8.34 Hz, 1H), 7.63-7.68 (m,1H), 8.39 (d, J=4.80 Hz, 1H), 11.32-11.46 (m, 1H), 13.68 (br. s., 1H).[M+H] Calc'd for C₁₅H₁₀Cl₂N₂O₂, 321; Found, 321.

Example 131: methyl2-(3,4-dichloro-5-fluorobenzyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 13% yield starting with3,4-dichloro-5-fluorobenzaldehyde according to the procedure for thepreparation of Example 55. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.02 (s, 3H),4.19 (s, 2H), 6.65-6.74 (m, 1H), 6.98 (d, J=7.33 Hz, 1H), 7.19 (s, 1H),7.64 (d, J=5.05 Hz, 1H), 8.55 (d, J=5.30 Hz, 1H), 9.40 (br. s., 1H).[M+H] Calc'd for C₁₆H₁₁FCl₂N₂O₂, 353; Found, 353.

Example 132:2-(3,4-dichloro-5-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

The title compound was prepared in 80% yield using methyl2-(3,4-dichloro-5-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 4.24 (s, 2H), 6.47-6.51 (m, 1H), 7.44-7.46 (m, 1H),7.47-7.49 (m, 1H), 7.54-7.58 (m, 1H), 8.39 (d, J=4.80 Hz, 1H),11.33-11.42 (m, 1H), 13.63-13.73 (m, 1H). [M+H] Calc'd forC₁₅H₉FCl₂N₂O₂, 339; Found, 339.

Example 133:methyl-2-(4-chloro-3-methylbenzyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 6% yield starting with3-methyl-4-chlorobenzaldehyde according to the procedure for thepreparation of Example 55. ¹H NMR (400 MHz, CD₃OD): δ 2.37 (3H, s), 4.05(3H, s), 4.23 (2H, s), 6.37 (1H, s), 7.13-7.16 (1H, m), 7.27 (1H, d,J=2.0 Hz), 7.32 (1H, d, J=8.0 Hz), 7.65 (1H, d, J=5.2 Hz), 8.38 (1H, d,J=5.2 Hz). [M+H] Calc'd for C₁₇H₁₅ClN₂O₂, 315; Found, 315.

Example 134:2-(4-chloro-3-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

The title compound was prepared in 80% yield usingmethyl-2-(4-chloro-3-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 2.30 (3H, s), 4.23 (2H, s), 6.48 (1H, s), 7.19-7.21(1H, m), 7.34-7.36 (2H, m), 7.62 (1H, d, J=5.6 Hz), 8.48 (1H, d, J=5.2Hz), 11.76 (1H, s). [M+H] Calc'd for C₁₆H₁₃ClN₂O₂, 301; Found, 301.

Example 135: methyl2-[4-chloro-3-(trifluoromethyl)benzyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in <5% yield starting with3-trifluoromethyl-4-chlorobenzaldehyde according to the procedure forthe preparation of Example 55. ¹H NMR (400 MHz, DMSO-d₆): δ 3.98 (3H,s), 4.33 (2H, s), 6.47 (1H, s), 7.51 (1H, d, J=4.8 Hz), 7.66-7.69 (2H,m), 7.91 (1H, s), 8.42 (1H, d, J=5.2 Hz), 11.46 (1H, s). [M+H] Calc'dfor C₁₇H₁₂ClF₃N₂O₂, 369; Found, 369.

Example 136:2-[4-chloro-3-(trifluoromethyl)benzyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 65% yield usingmethyl-2-(4-chloro-3-trifluoromethylbenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 4.32 (2H, s), 6.48 (1H, s), 7.49 (1H, d, J=5.2 Hz),7.66-7.69 (2H, m), 7.90 (1H, s), 8.40 (1H, d, J=4.4 Hz), 11.45 (1H, s).[M+H] Calc'd for C₁₆H₁₀ClF₃N₂O₂, 355; Found, 355.

Example 137: Methyl2-[4-chloro-3-(cyclopropylmethoxy)benzyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in <5% yield starting with3-(cyclopropylmethoxy)-4-chlorobenzaldehyde according to the procedurefor the preparation of Example 55. 1 H NMR (400 MHz, CD₃OD): δ 0.33-0.36(2H, m), 0.55-0.60 (2H, m), 1.24-1.27 (1H, m), 3.87 (2H, d, J=6.4 Hz),4.03 (3H, s), 4.21 (2H, s), 6.36 (1H, s), 6.84-6.86 (1H, m), 7.01 (1H,d, J=1.6 Hz), 7.28 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=5.2 Hz), 8.34 (1H,d, J=5.2 Hz). [M+H] Calc'd for C₂₀H₁₉ClN₂O₃, 371; Found, 371.

Example 138:2-[4-chloro-3-(cyclopropylmethoxy)benzyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 65% yield usingmethyl-2-(4-chloro-3-trifluoromethylbenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.33-0.36 (2H, m), 0.55-0.60 (2H, m), 1.22-1.26(1H, m), 3.87 (2H, d, J=6.4 Hz), 4.21 (2H, s), 6.48 (1H, s), 6.90-6.92(1H, m), 7.21 (1H, d, J=2.0 Hz), 7.34 (1H, d, J=8.0 Hz), 7.61 (1H, d,J=5.2 Hz), 8.47 (1H, d, J=5.2 Hz), 11.39 (1H, s). [M+H] Calc'd forC₁₉H₁₇ClN₂O₃, 357; Found, 357.

Example 139:methyl-2-[4-chloro-3-(2,2,2-trifluoroethoxy)benzyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in <5% yield starting with3-(2,2,2-trifluoroethoxy)-4-chlorobenzaldehyde according to theprocedure for the preparation of Example 55. ¹H NMR (400 MHz, CD₃OD): δ4.06 (3H, s), 4.28 (2H, s), 4.58-4.64 (2H, m), 6.41 (1H, s), 7.01-7.04(1H, m), 7.18 (1H, d, J=2.0 Hz), 7.40 (1H, d, J=8.4 Hz), 7.65 (1H, d,J=4.8 Hz), 8.38 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₈H₁₄F₃ClN₂O₃, 399;Found, 399.

Example 140:2-[4-chloro-3-(2,2,2-trifluoroethoxy)benzyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 80% yield usingmethyl-2-[4-chloro-3-(2,2,2-tri-fluoroethoxy)benzyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 4.23 (2H, s), 4.81-4.88 (2H, m), 6.41 (1H, s),7.02-7.05 (1H, m), 7.35 (1H, d, J=1.2 Hz), 7.41 (1H, d, J=8.0 Hz), 7.52(1H, d, J=5.2 Hz), 8.41 (1H, d, J=4.8 Hz), 11.45 (1H, s). [M+H] Calc'dfor C₁₇H₁₂F₃ClN₂O₃, 385; Found, 385.

Example 141:methyl-2-[4-chloro-3-(trifluoromethoxy)benzyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate

The title compound was prepared in 8% yield starting with3-(trifluoromethoxy)-4-chlorobenzaldehyde according to the procedure forthe preparation of Example 59. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.03 (s,3H), 4.24 (s, 2H), 6.64-6.82 (m, 1H), 7.15 (d, J=10.11 Hz, 1H), 7.46 (d,J=8.08 Hz, 2H), 7.63-7.77 (m, 1H), 8.53 (d, J=5.31 Hz, 1H), 9.40-9.57(m, 1H). [M+H] Calc'd for C₁₇H₁₂F₃ClN₂O₃, 385; Found, 385.

Example 142:2-[4-chloro-3-(trifluoromethoxy)benzyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylicacid

The title compound was prepared in 92% yield usingmethyl-2-[4-chloro-3-(trifluoro-methoxy)benzyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylateaccording to the procedure for the preparation in Example 5. ¹H NMR (400MHz, DMSO-d₆): δ ppm 4.28 (s, 3H), 6.40-6.46 (m, 1H), 7.37-7.43 (m, 1H),7.48 (d, J=4.80 Hz, 1H), 7.58-7.65 (m, 3H), 8.39 (d, J=4.80 Hz, 1H),11.38 (br. s., 1H), 13.67 (s, 1H). [M+H] Calc'd for C₁₇H₁₂ClN₂O₃, 371;Found, 371.

Example 143:2-[4-chloro-benzyl]-N-methyl-1H-pyrrolo[3,2-b]pyridine-7-carboxamide

To a vial charged with2-(4-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (75 mg,0.262 mmol) in DMF (2 mL) was added HATU (150 mg, 0.393 mmol), DIEA (191μL, 1 mmol) and MeNH₂—HCl (26 mg, 0.393 mmol). The reaction was allowedto stir for 16 hr at ambient temp. The crude mixture was purified byprep-HPLC (5-95% gradient of ACN in water with 0.1% HCO₂H) to afford thetitle compound as orange solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm2.81-2.92 (m, 3H), 4.12-4.27 (m, 2H), 6.28-6.37 (m, 1H), 7.36 (m, 5H),8.32 (d, J=5.05 Hz, 1H), 8.70-8.83 (m, 1H), 11.30 (br. s., 1H). [M+H]Calc'd for C₁₆H₁₄ClN₃O, 300; Found, 300.

Example 144:2-[4-chloro-3-(trifluoromethoxy)benzyl]-N-methyl-1H-pyrrolo[3,2-b]-pyridine-7-carboxamide

The title compound was prepared in 49% yield using2-[4-chloro-3-(trifluoromethoxy)-benzyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid according to the procedure for the preparation in Example 143. ¹HNMR (400 MHz, CDCl₃): δ ppm 2.89-3.20 (m, 3H), 4.05-4.14 (m, 1H), 4.24(s, 2H), 6.60-6.80 (m, 1H), 7.05-7.18 (m, 1H), 7.41-7.58 (m, 2H),7.93-8.12 (m, 1H), 8.36 (br. s., 1H), 10.24 (s, 1H). [M+H] Calc'd forC₁₇H₁₃F₃ClN₃O₂, 384; Found, 384.

II. Biological Evaluation Example 1: In Vitro Enzyme Inhibition Assay

This assay determines the ability of a test compound to inhibit Jarid1A,Jarid1B, JMJD2C, and JMJD2A demethylase activity. Baculovirus expressedJarid1A (GenBank Accession #NM_001042603, AA1-1090) was purchased fromBPS Bioscience (Cat#50110). Baculovirus expressed Jarid1B (GenBankAccession #NM_006618, AA 2-751) was purchased from BPS Bioscience (Cat#50121) or custom made by MolecularThroughput. Baculovirus expressedJMJD2C (GenBank Accession #BC143571, AA 2-372) was purchased from BPSBioscience (Cat#50105). Baculovirus expressed JMJD2A (GenBank Accession#NM_014663, AA 1-350) was purchased from BPS Bioscience (Cat#50123).

Jarid1A Assay

The enzymatic assay of Jarid1A activity is based upon TimeResolved-Fluorescence Resonance Energy Transfer (TR-FRET) detection. Theability of test compounds to inhibit the activity of Jarid1A wasdetermined in 384-well plate format under the following reactionconditions: 1 nM Jarid1A, 300 nM H3K4me3-biotin labeled peptide (Anaspeccat #64357), 2 μM α-ketoglutaric acid in assay buffer of 50 mM HEPES,pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-mono- or di-methylated histone H3 lysine 4 (H3K4me1-2)antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detectionbuffer (PerkinElmer) at a final concentration of 25 nM and 1 nM,respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K4me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO was addedto each well of plate, followed by the addition of 2 μl of 3 nM Jarid1Ato initiate the reaction. The reaction mixture was incubated at roomtemp for 30 min, and terminated by the addition of 6 μl of 5 mM EDTA inLANCE detection buffer containing 50 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K4me1-2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hrincubation at room temp. A ratio was calculated (665/615) for each welland fitted to determine inhibition constant (IC₅₀).

Jarid1B Assay

The ability of test compounds to inhibit the activity of Jarid1B wasdetermined in 384-well plate format under the following reactionconditions: 0.8 nM Jarid1B, 300 nM H3K4me3-biotin labeled peptide(Anaspec cat #64357), 2 μM α-ketoglutaric acid in assay buffer of 50 mMHEPES, pH 7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-mono- or di-methylated histone H3 lysine 4 (H3K4me1-2)antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detectionbuffer (PerkinElmer) at a final concentration of 25 nM and 1 nM,respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K4me3-biotin labeled peptide and 6 μM α-ketoglutaric acidwith 2 μl of 11-point serial diluted inhibitor in 3% DMSO was added toeach well of the plate, followed by the addition of 2 μl of 2.4 nMJarid1B to initiate the reaction. The reaction mixture was incubated atroom temp for 30 min, and terminated by the addition of 6 μl of 5 mMEDTA in LANCE detection buffer containing 50 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K4me1-2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hrincubation at room temp. A ratio was calculated (665/615) for each welland fitted to determine inhibition constant (IC₅₀).

JMJD2C Assay

The ability of test compounds to inhibit the activity of JMJD2C wasdetermined in 384-well plate format under the following reactionconditions: 0.3 nM JMJD2C, 300 nM H3K9me3-biotin labeled peptide(Anaspec cat #64360), 2 μM α-ketoglutaric acid in assay buffer of 50 mMHEPES, pH 7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody(PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer(PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K9me3-biotin labeled peptide and 6 μM α-ketoglutaric acidwith 2 μl of 11-point serial diluted inhibitor in 3% DMSO were added toeach well of the plate, followed by the addition of 2 μl of 0.9 nMJMJD2C to initiate the reaction. The reaction mixture was incubated atroom temp for 30 min, and terminated by the addition of 6 μl of 5 mMEDTA in LANCE detection buffer containing 100 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hrincubation at room temp. A ratio was calculated (665/615) for each welland fitted to determine inhibition constant (IC₅₀).

JMJD2A Assay

The ability of test compounds to inhibit the activity of JMJD2A wasdetermined in 384-well plate format under the following reactionconditions: 2 nM JMJD2A, 300 nM H3K9me3-biotin labeled peptide (Anaspeccat #64360), 2 μM α-ketoglutaric acid in assay buffer of 50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody(PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer(PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K9me3-biotin labeled peptide and 6 μM α-ketoglutaric acidwith 2 μl of 11-point serial diluted inhibitor in 3% DMSO were added toeach well of plate, followed by the addition of 2 μl of 6 nM JMJD2A toinitiate the reaction. The reaction mixture was incubated at roomtemperature for 30 minutes, and terminated by the addition of 6 μl of 5mM EDTA in LANCE detection buffer containing 100 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hrincubation at room temp. A ratio was calculated (665/615) for each welland fitted to determine inhibition constant (IC₅₀).

The ability of the compounds disclosed herein to inhibit demethylaseactivity was quantified and the respective IC₅₀ value was determined.Table 3 provides the IC₅₀ values of various compounds disclosed herein.

TABLE 3 Chemical IC₅₀ IC₅₀ IC₅₀ IC₅₀ Synthesis Jarid1A Jarid1B JMJD2CJMJD2A Example NAME (μM) (μM) (μM) (μM) 1 3-chloro-1H-pyrrolo[3,2-b]- CD C pyridine-7-carboxylic acid 2 2-phenyl-1H-pyrrolo[3,2-b]- B B B Bpyridine-7-carboxylic acid 3 2-(2-methylphenyl)-1H-pyrrolo- B B B A[3,2-b]pyridine-7-carboxylic acid 6 methyl 2-benzyl-1H-pyrrolo- D D D[3,2-b]pyridine-7-carboxylate 7 2-benzyl-1H-pyrrolo-[3,2-b]- B B B Bpyridine-7-carboxylic acid 8 2-propyl-1H-pyrrolo[3,2-b]- C C Apyridine-7-carboxylic acid 10 2-(hydroxymethyl)-1H-pyrrolo- B B B[3,2-b]pyridine-7-carboxylic acid 11 methyl 2-cyclopropyl-1H- D D Dpyrrolo-[3,2-b]pyridine-7- carboxylate 12 2-cyclopropyl-1H-pyrrolo[3,2-C C A b]pyridine-7-carboxylic acid 5 2-(2-hydroxypropan-2-yl)-1H- B B Apyrrolo[3,2-b]pyridine-7- carboxylic acid 4 methyl2-(2-hydroxypropan-2-yl)- D D D 1H-pyrrolo[3,2-b]-pyridine-7-carboxylate 13 methyl 2-(1-hydroxycyclo-hexyl)- D D D1H-pyrrolo[3,2-b]-pyridine-7- carboxylate 14 2-(1-hydroxycyclohexyl)-1H-B B B pyrrolo[3,2-b]pyridine-7- carboxylic acid 15 methyl2-(4-methoxy-2- D D D methylphenyl)-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 17 methyl 2-(1-hydroxyethyl)-1H- D D Dpyrrolo[3,2-b]pyridine- 7-carboxylate 18 2-(1-hydroxyethyl)-1H-pyrrolo-B B A [3,2-b]pyridine-7-carboxylic acid 162-(4-methoxy-2-methyl-phenyl)- B B B 1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 20 2-[hydroxy(phenyl)methyl]-1H- A A Apyrrolo[3,2-b]pyridine-7- carboxylic acid 222-[hydroxy-(3-methylphenyl)- A A A methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 24 2-[hydroxy-(3-methoxy- A A B Bphenyl)methyl]-1H-pyrrolo [3,2-b]pyridine7-carboxylic acid 21 methyl2-[hydroxy-(3-methyl- C D D phenyl)methyl]-1H-pyrrolo-[3,2-b]-pyridine-7-carboxylate 20 methyl 2-[hydroxy(phenyl)- C D Dmethyl]-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate 9 methyl2-(hydroxymethyl)-1H- D D D pyrrolo[3,2-b]pyridine-7- carboxylate 23methyl 2-[hydroxy-(3-methoxy- phenyl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate 25 methyl 2-(1-hydroxypropyl)-1H- D D Dpyrrolo[3,2-b]pyridine-7- carboxylate 27 2-(1-hydroxycyclopentyl)-1H- AA A pyrrolo[3,2-b]pyridine-7- carboxylic acid 292-cyclopentyl-1H-pyrrolo[3,2-b]- B B A pyridine-7-carboxylic acid 28methyl 2-cyclopentyl-1H-pyrrolo- D D D [3,2-b]pyridine-7-carboxylate 262-(1-hydroxypropyl)-1H-pyrrolo- A B A [3,2-b]pyridine-7-carboxylic acid30 2-(1-hydroxy-2-methylpropyl)- B A A 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 31 methyl 2-(1-hydroxy-2-methyl-propyl)-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate 332-[cyclopropyl(hydroxy)-methyl]- A A A 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 32 methyl 2-[cyclopropyl- (hydroxy)methyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 34 2-[(3-methoxyphenyl)methyl]- A B B1H-pyrrolo[3,2-b]pyridine-7- carboxylic acid 35 methyl2-[(3-methylphenyl)- methyl]-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate37 methyl 2-(2-cyclopropyl-1- hydroxyethyl)-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate 36 2-[(3-methylphenyl)methyl]-1H- A B Apyrrolo[3,2-b]pyridine-7- carboxylic acid 38 2-(2-cyclopropyl-1- A A Ahydroxyethyl)-1H-pyrrolo[3,2- b]pyridine-7-carboxylic acid 392-(phenoxymethyl)-1H- A A A B pyrrolo[3,2-b]pyridine-7- carboxylic acid41 2-(methoxymethyl)-1H- B B A pyrrolo[3,2-b]pyridine-7- carboxylic acid40 methyl 2-(methoxymethyl)-1H- pyrrolo[3,2-b]pyridine- 7-carboxylate 432-[hydroxy(oxan-4-yl)methyl]- A A B B 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 42 methyl 2-[hydroxy(oxan-4-yl)-methyl]-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate 442-[(4-chlorophenyl)methyl]-1H- A A B pyrrolo[3,2-b]pyridine-7-carboxylic acid 46 2-(1-hydroxy-1-phenylethyl)-1H- A B Bpyrrolo[3,2-b]pyridine-7- carboxylic acid 45 methyl 2-(1-hydroxy-1-phenylethyl)-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate 47 methyl2-[hydroxy-(2-methyl- pyrazol-3-yl)methyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 49 methyl 2-[hydroxy-(1-methyl-pyrazol-4-yl)methyl]-1H-pyrrolo- [3,2-b]pyridine-7-carboxylate 51 methyl2-(cyclopentylmethyl)- 1H-pyrrolo[3,2-b]pyridine- 7-carboxylate 482-[hydroxy-(2-methylpyrazol-3- A A A yl)-methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 52 2-(cyclopentylmethyl)-1H- A B Apyrrolo[3,2-b]pyridine- 7-carboxylic acid 53 methyl2-(cyclohexylmethyl)-1H- pyrrolo[3,2-b]pyridine- 7-carboxylate 542-(cyclohexylmethyl)-1H- B B A pyrrolo[3,2-b]pyridine- 7-carboxylic acid50 2-[hydroxy-(1-methylpyrazol-4- A B B yl)methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 55 methyl 2-[[4-(trifluoromethyl)-phenyl]methyl]-1H-pyrrolo [3,2-b]-pyridine-7-carboxylate 562-[[4-(trifluoromethyl)phenyl]- B B B methyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 57 methyl 2-(2-cyanoethyl)-1H-pyrrolo[3,2-b]pyridine-7- carboxylate 582-(2-cyanoethyl)-1H-pyrrolo[3,2- B B A b]pyridine-7-carboxylic acid 592-[(4-methoxyphenyl)methyl]- B B A 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 60 2-[(4-fluorophenoxy)methyl]-1H- A A Bpyrrolo[3,2-b]pyridine-7- carboxylic acid 61 Methyl2-[(4-methylphenoxy)- methyl]-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate62 2-[(4-methylphenoxy)methyl]- B B B 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 63 Methyl 2-[(4-chlorophenoxy)-methyl]-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate 642-[(4-chlorophenoxy)methyl]-1H- A A A pyrrolo[3,2-b]pyridine-7-carboxylic acid 66 2-[(2-methylphenoxy)methyl]- A A B1H-pyrrolo[3,2-b]pyridine-7- carboxylic acid 65 methyl2-[(2-methylphenoxy)- methyl]-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate68 2-[[4-(trifluoromethyl)-phenoxy]- A A B methy]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 67 methyl 2-[[4-(trifluoromethyl)-phenoxy]methyl]-1H-pyrrolo- [3,2-b]-pyridine-7-carboxylate 702-(2-phenylethyl)-1H-pyrrolo- B B A [3,2-b]pyridine-7-carboxylic acid 69methyl 2-(2-phenylethyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylate 722-[(2-chlorophenyl)- A A B hydroxymethyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylic acid 71 methyl 2-[(2-chlorophenyl)-hydroxymethyl]-1H-pyrrolo- [3,2-b]pyridine-7-carboxylate 73 methyl2-[(3-methylphenoxy)- methyl]-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate74 2-[(3-methylphenoxy)methyl]- A A A 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 75 methyl 2-(2,3-dihydro-1-benzo-furan-5-yloxymethyl)-1H- pyrrolo-[3,2-b]pyridine-7- carboxylate 762-(2,3-dihydro-1-benzofuran- A A B 5-yloxymethyl)-1H-pyrrolo-[3,2-b]pyridine-7-carboxylic acid 77 methyl 2-[(2-chlorophenyl)-methyl]-1H-pyrrolo-[3,2- b]pyridine-7-carboxylate 782-[(2-chlorophenyl)methyl]-1H- A A A pyrrolo[3,2-b]pyridine-7-carboxylic acid 79 2-[(3-fluorophenoxy)methyl]-1H- A A Apyrrolo[3,2-b]pyridine-7- carboxylic acid 802-[(3-chlorophenoxy)methyl]-1H- A A B pyrrolo[3,2-b]pyridine-7-carboxylic acid 81 2-[(3,5-difluorophenoxy)- A A Amethyl]-1H-pyrrolo[3,2- b]pyridine-7-carboxylic acid 822-[(3,5-dimethylphenoxy)- A A B methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 83 2-[(3,5-dichlorophenoxy)- A A Bmethyl]-1H-pyrrolo[3,2- b]pyridine-7-carboxylic acid 842-(1-phenoxyethyl)-1H- A A A pyrrolo[3,2-b]pyridine-7- carboxylic acid85 2-(1-phenoxybutyl)-1H- A A B pyrrolo[3,2-b]pyridine-7- carboxylicacid 86 2-(3-methyl-1-phenoxybutyl)-1H- B B C pyrrolo[3,2-b]pyridine-7-carboxylic acid 87 methyl 2-[(2-chlorophenyl)-propoxymethyl]-1H-pyrrolo- [3,2-b]pyridine-7-carboxylate 882-[(2-chlorophenyl)- A A C propoxymethyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylic acid 89 methyl 2-[(2,4-dichlorophenyl)-methyl]-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate 902-[(2,4-dichlorophenyl)methyl]- A A B 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 91 methyl 2-(1-benzofuran-2-yl)-1H-pyrrolo[3,2-b]pyridine-7- carboxylate 92 2-(1-benzofuran-2-yl)-1H- B B Bpyrrolo-[3,2-b]pyridine-7- carboxylic acid 932-[(4-methoxyphenoxy)methyl]- B A B 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 94 2-[(2-chlorophenoxy)methyl]-1H- B B Cpyrrolo[3,2-b]pyridine-7- carboxylic acid 952-[(2-fluorophenoxy)methyl]-1H- B B B pyrrolo[3,2-b]pyridine-7-carboxylic acid 96 2-[(2-chloro-4-fluorophenoxy)- A A Bmethyl]-1H-pyrrolo[3,2-b]- pyridine-7-carboxylic acid 972-[(4-acetamidophenoxy)- B B B methyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylic acid 98 2-[(4-cyanophenoxy)methyl]-1H- A BB pyrrolo[3,2-b]pyridine-7- carboxylic acid 992-(pyrrolidin-1-ylcarbonyl)-1H- A A A A pyrrolo[3,2-b]pyridine-7-carboxylic acid 100 methyl 2-[(4-fluorophenyl)-methyl]pyrrolo[3,2-b]pyridine- 7-carboxylate 1012-[(4-fluorophenyl)methyl]- A A A pyrrolo[3,2-b]pyridine- 7-carboxylicacid 102 methyl 2-[1-(4-fluorophenyl)-1- hydroxyethyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 103 2-[1-(4-fluorophenyl)-1- A A Ahydroxyethyl]-1H-pyrrolo- [3,2-b]pyridine-7-carboxylic acid 104 methyl2-(1,2,3,4-tetrahydro- quinolylcarbonyl)pyrrolo[3,2-b]-pyridine-7-carboxylate 105 2-(1,2,3,4-tetrahydroquinolyl- B C Ccarbonyl)pyrrolo[3,2-b]-pyridine- 7-carboxylic acid 106 methyl2-(indolinylcarbonyl)- pyrrolo[3,2-b]pyridine- 7-carboxylate 1072-(indolinylcarbonyl)pyrrolo- A A B [3,2-b]pyridine-7-carboxylic acid108 methyl 2-(piperidylcarbonyl)- pyrrolo[3,2-b]pyridine- 7-carboxylate109 2-(piperidylcarbonyl)pyrrolo- B B B [3,2-b]pyridine-7-carboxylicacid 110 2-[1-(4-fluorophenyl)ethyl]-1H- B B B pyrrolo[3,2-b]pyridine-7-carboxylic acid 111 methyl-2-(3-chloro-4-fluoro-benzyl)-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate 1122-(3-chloro-4-fluorobenzyl)-1H- A A A pyrrolo[3,2-b]pyridine-7-carboxylic acid 113 methyl 2-(4-chloro-3-fluorobenzyl)-1H-pyrrolo[3,2-b]- pyridine-7-carboxylate 1142-(4-chloro-3-fluorobenzyl)-1H- A A A pyrrolo[3,2-b]pyridine-7-carboxylic acid 115 methyl 2-[(3-phenyl- pyrrolidinyl)carbonyl]pyrrolo-[3,2-b]pyridine-7-carboxylate 116 2-[(3-phenylpyrrolidinyl)- A A Bcarbonyl]pyrrolo[3,2-b]pyridine- 7-carboxylic acid 117 methyl2-[(4,4-dimethyl- piperidyl)carbonyl]pyrrolo-[3,2-b]-pyridine-7-carboxylate 118 2-[(4,4-dimethylpiperidyl)- A A Acarbonyl]pyrrolo[3,2-b]pyridine- 7-carboxylic acid 119 methyl2-[(3-phenylpiperidyl)- carbonyl]pyrrolo[3,2-b]pyridine- 7-carboxylate120 2-[(3-phenylpiperidyl)- B B B carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylic acid 121 methyl 2-(2-1,2,3,4-tetrahydro-isoquinolylcarbonyl)pyrrolo- [3,2-b]pyridine-7-carboxylate 1222-(2-1,2,3,4-tetrahydroiso- A A B quinolylcarbonyl)pyrrolo[3,2-b]-pyridine-7-carboxylic acid 123 methyl 2-[(2,2-dimethyl-pyrrolidinyl)carbonyl]pyrrolo- [3,2-b]pyridine-7-carboxylate 1242-[(2,2-dimethylpyrrolidinyl)- B A B carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylic acid 126 2-(3,4-fluorobenzyl)-1H- C C A Apyrrolo[3,2-b]pyridine-7- carboxylic acid 1282-(4-chloro-3-methoxybenzyl)- C C A B 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 130 2-(3,4-dichlorobenzyl)-1H- C C A Bpyrrolo[3,2-b]pyridine-7- carboxylic acid 1322-(3,4-dichloro-5-fluorobenzyl)- C C B B 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 134 2-(4-chloro-3-methylbenzyl)-1H- C B A Bpyrrolo[3,2-b]pyridine-7- carboxylic acid 1362-[4-chloro-3-(trifluoromethyl)- C C A B benzyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid 138 2-[4-chloro-3-(cyclopropyl- B A A Cmethoxy)benzyl]-1H-pyrrolo- [3,2-b]pyridine-7-carboxylic acid 1422-[4-chloro-3-(trifluoro- B A A B methoxy)benzyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylic acid Note: Biochemical assay IC₅₀ data aredesignated within the following ranges: A: ≤0.10 μM; B: >0.10 μM to ≤1.0μM; C: >1.0 μM to ≤10 μM; D: >10 μM

Example 2a: In Vitro Cell-Based Assay—ZR-75-1 Cell Line

An assay to measure the degree of cellular inhibition of KDM5A and KDM5Bwas developed. This quantitative immuno-blotting assay measures theamount tri-methylated histone H3 at amino acid Lysine number 4, aspecific substrate and product of the direct enzymatic activity of thehistone demethylases KDM5A and KDM5B from extracts of the ZR-75-1 breastcancer cell line.

Assay Principle

This assay is a fluorometric immunoassay for the quantification oftri-methyl H3K4 extracted from cells treated with test compound and isused as a measure of the cellular inhibition of KDM5A/B.

Assay Method

ZR-75-1 (PTEN null, ER+) breast cancer cells numbering 50,000 (ATCC)were seeded into each well of a 96-well tissue culture treated plate andthen exposed to an 11 point dilution of test compound with finalconcentration ranges of test compound ranging from 1250 μM to 10 nM.Cells were left in the presence of test compound for 72 hr. Extractswere prepared containing all of the cellular histone material usingdetergent based lysis and sonication methods. These lysates weresubsequently normalized for total protein content using a colorimetricbicinchonic acid assay (MicroBCA Pierce/Thermo Scientific). Normalizedcell extracts were then subjected to typical immuno-blotting proceduresusing NuPage reagents (Life Technologies). Electrophoretically separatedhistones were then transferred and immobilized using polyvinylidenedifluoride membrane (Immobilon-FL Millipore). The amount oftri-methylated lysine 4 of histone H3 was detected using an antibodyspecific to the tri-methylated state (Cell Signaling Technologies) andquantified on an infrared imager using a densitometry software package(Odyssey CLx, Image Studio, Li-Cor). This background subtracteddensitometry value was reported as a ration of the GAPDH amount for thatsample and then calculated as a percent of the DMSO treated sample. Thesoftware package XL-fit (IDBS) was then used to calculate a relativeIC₅₀ value for the dilution series of a given test compound according tothe equation:fit=(D+((Vmax*(x{circumflex over ( )}n))/((x{circumflex over( )}n)+(Km{circumflex over ( )}n)))).

Example 2b: In Vitro Cell-Based Assay—KYSE-150 Cell Line

The primary cellular assay for JMJD2C inhibition is an assay whichmeasures cellular proliferation via Bromodeoxyuridine (BrdU)incorporation after 168 hr of compound incubation. This assay is aquantitative ELISA assay measuring DNA incorporation of BrdU duringS-phase as a direct readout of cellular proliferation. The KYSE-150 cellline is a JMJD2C gene amplified cell line.

Assay Principle

This is a colorimetric immunoassay for the quantification of cellproliferation. Cells treated for 168 hr with test compounds are assayedfor their ability to go through S-phase as a measure of theirproliferative potential.

Assay Method

The human KYSE-150 (SMAD4 mut, TP53 mut) esophageal carcinoma cell linewas seeded at 2,000 cells/well on a 96-well tissue culture treatedplate. After an overnight incubation, cells were treated with a testcompound in an 11 point dilution series with final concentrationsranging from 100 μM to 2 nM. Cells were then incubated in the presenceof compound for 168 hr. After compound incubation, the cells wereassayed using a BrdU Cell Proliferation ELISA (Roche). The cells werefirst incubated with BrdU labeling reagent for 2 hr. After 2 hr, theseBrdU incorporated cells were fixed and denatured, probed with ananti-BrdU-Peroxidase antibody for 1.5 hr and washed. Finally, atetramethylbenzidine peroxidase substrate was added to each well for 15min followed by H2SO₄ stop solution. The plate is read at 450 nm, andthe raw optical density data is transferred into XLFit (IDBS) for IC₅₀calculation using the formula:fit=(D+((Vmax*(x{circumflex over ( )}n))/((x{circumflex over( )}n)+(Km{circumflex over ( )}n))))

Table 4 provides the cellular IC₅₀ values of various compounds disclosedherein.

TABLE 4 Chemical Synthesis IC₅₀ ZR-75-1 IC₅₀ KYSE-150 Example Namecell-MOA (μM) cell-BrdU(μM) 6 methyl 2-benzyl-1H-pyrrolo[3,2-b]- Dpyridine-7-carboxylate 7 2-benzyl-1H-pyrrolo[3,2-b]pyridine-7- Dcarboxylic acid 34 2-[(3-methoxyphenyl)methyl]-1H- Dpyrrolo[3,2-b]pyridine-7-carboxylic acid 362-[(3-methylphenyl)methyl]-1H- D pyrrolo[3,2-b]pyridine-7-carboxylicacid 42 methyl 2-[hydroxy(oxan-4-yl)methyl]- D1H-pyrrolo[3,2-b]pyridine-7-carboxylate 442-[(4-chlorophenyl)methyl]-1H- D pyrrolo[3,2-b]pyridine-7-carboxylicacid 46 2-(1-hydroxy-1-phenylethyl)-1H- Dpyrrolo[3,2-b]pyridine-7-carboxylic acid 45 methyl2-(1-hydroxy-1-phenylethyl)-1H- D pyrrolo[3,2-b]pyridine-7-carboxylate47 methyl 2-[hydroxy-(2-methylpyrazol-3- Dyl)methyl]-1H-pyrrolo[3,2-b]pyridine- 7-carboxylate 482-[hydroxy-(2-methylpyrazol-3-yl)- D methyl]-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid 50 2-[hydroxy-(1-methylpyrazol-4-yl)- Dmethyl]-1H-pyrrolo[3,2-b]pyridine-7- carboxylic acid 602-[(4-fluorophenoxy)methyl]-1H- C pyrrolo[3,2-b]pyridine-7-carboxylicacid 64 2-[(4-chlorophenoxy)methyl]-1H- Cpyrrolo[3,2-b]pyridine-7-carboxylic acid 662-[(2-methylphenoxy)methyl]-1H- D pyrrolo[3,2-b]pyridine-7-carboxylicacid 72 2-[(2-chlorophenyl)-hydroxymethyl]-1H- Dpyrrolo[3,2-b]pyridine-7-carboxylic acid 742-[(3-methylphenoxy)methyl]-1H- D pyrrolo[3,2-b]pyridine-7-carboxylicacid 101 2-[(4-fluorophenyl)methyl]pyrrolo-[3,2- Db]pyridine-7-carboxylic acid 125 Methyl 2-(3,4-difluorobenzyl)-1H- Cpyrrolo[3,2-b]pyridine-7-carboxylate 127Methyl-2-(4-chloro-3-methoxybenzyl)- A1H-pyrrolo[3,2-b]pyridine-7-carboxylate 129Methyl-2-(3,4-dichlorobenzyl)-1H- A pyrrolo[3,2-b]pyridine-7-carboxylate131 Methyl-2-(3,4-dichloro-5-fluoro-benzyl)- A1H-pyrrolo[3,2-b]pyridine-7-carboxylate 133Methyl-2-(4-chloro-3-methylbenzyl)-1H- Bpyrrolo[3,2-b]pyridine-7-carboxylate 135Methyl-2-[4-chloro-3-(trifluoro- A methyl)benzyl]-1H-pyrrolo[3,2-b]-pyridine-7-carboxylate 137 Methyl 2-[4-chloro-3- A(cyclopropylmethoxy)benzyl]-1H- pyrrolo[3,2-b]pyridine-7-carboxylate 139methyl-2-[4-chloro-3-(2,2,2- A trifluoroethoxy)benzyl]-1H-pyrrolo-[3,2-b]pyridine-7-carboxylate 141 methyl-2-[4-chloro-3- A(trifluoromethoxy)benzyl]-1H- pyrrolo[3,2-b]pyridine-7-carboxylate 1432-[4-chloro-benzyl]-N-methyl-1H- B pyrrolo[3,2-b]pyridine-7-carboxamide144 2-[4-chloro-3-(trifluoromethoxy)- Abenzyl]-N-methyl-1H-pyrrolo[3,2-b]- pyridine-7-carboxamide Note:Cellular assay IC₅₀ data are designated within the following ranges: A:≤0.10 μM; B: >0.10 μM to ≤1.0 μM; C: >1.0 μM to ≤10 μM; D: >10 μM

Example 3: In Vivo Xenograft Study

Time release pellets containing 0.72 mg 17-13 Estradiol aresubcutaneously implanted into nu/nu mice. MCF-7 cells are grown in RPMIcontaining 10% FBS at 5% CO₂, 37° C. Cells are spun down andre-suspended in 50% RPMI (serum free) and 50% Matrigel at 1×10⁷cells/mL. MCF-7 cells are subcutaneously injected (100 μL/animal) on theright flank 2-3 days post-pellet implantation and tumor volume 1/2(length×width²) is monitored bi-weekly. When tumors reach an averagevolume of ˜200 mm³ animals are randomized and treatment is started.Animals are treated with vehicle or compound daily for 4 weeks. Tumorvolume and body weight are monitored bi-weekly throughout the study. Atthe conclusion of the treatment period, plasma and tumor samples aretaken for pharmacokinetic and pharmacodynamic analyses, respectively.

III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral Tablet

A tablet is prepared by mixing 48% by weight of a compound of Formula(I) or a pharmaceutically acceptable salt thereof, 45% by weight ofmicrocrystalline cellulose, 5% by weight of low-substitutedhydroxypropyl cellulose, and 2% by weight of magnesium stearate.

Tablets are prepared by direct compression. The total weight of thecompressed tablets is maintained at 250 mg-500 mg.

We claim:
 1. A compound having the structure of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein, Y is C(O)N(H)CN,C(O)N(H)OH or tetrazolyl; R¹ is hydrogen or alkyl; G is X—R², wherein Xis a bond, alkylene, alkylene-O—, —C(O)—, —C(O)—NH—, —NH—, —NH—C(O)—,—O—, —S—, or —SO₂—; R² is selected from carbocyclyl, heterocyclyl, aryl,or heteroaryl; X¹ is a bond, —C(O)—, —C(O)—NH—, —NH—, —NH—C(O)—, —O—,—S—, or —SO₂—; and R³ is hydrogen.
 2. The compound of claim 1, wherein Yis —CO₂R¹ and R¹ is hydrogen.
 3. The compound of claim 1, wherein Y is—CO₂R¹ and R¹ is alkyl.
 4. The compound of claim 1, wherein Y is—C(O)N(H)CN.
 5. The compound of claim 1, wherein X is a bond and R² isaryl.
 6. The compound of claim 1, wherein X is alkylene and R² is aryl.7. The compound of claim 6, wherein alkylene is substituted with —OH,alkoxy, alkylamino, or dialkylamino.
 8. The compound of claim 1, whereinX is a C₁-C₃ alkylene and R² is aryl.
 9. The compound of claim 1,wherein X is a bond and R² is carbocyclyl.
 10. The compound of claim 9,wherein R² is C₃-C₇ carbocyclyl.
 11. The compound of claim 10, whereinthe carbocyclyl is a 1-hydroxy carbocyclyl.
 12. The compound of claim 1,wherein X is a bond and R² is heteroaryl.
 13. The compound of claim 1,wherein X is a bond and R² is heterocyclyl.
 14. The compound of claim 1,wherein X is alkylene and R² is carbocyclyl.
 15. The compound of claim14, wherein alkylene is substituted with —OH, alkoxy, alkylamino, ordialkylamino.
 16. The compound of claim 14, wherein R² is C₃-C₇carbocyclyl.
 17. The compound of claim 1, wherein X is C₁-C₃ alkyleneand R² is carbocyclyl.
 18. The compound of claim 17, wherein R² is C₃-C₇carbocyclyl.
 19. The compound of claim 1, wherein X is alkylene and R²is heteroaryl.
 20. The compound of claim 19, wherein alkylene issubstituted with —OH, alkoxy, alkylamino, or dialkylamino.
 21. Thecompound of claim 1, wherein X is C₁-C₃ alkylene and R² is heteroaryl.22. The compound of claim 1, wherein X is alkylene and R² isheterocyclyl.
 23. The compound of claim 22, wherein alkylene issubstituted with —OH, alkoxy, alkylamino, or dialkylamino.
 24. Thecompound of claim 1, wherein X is C₁-C₃ alkylene and R² is heterocyclyl.25. The compound of claim 1, wherein X is —C(O)— and R² is aryl.
 26. Thecompound of claim 1, wherein X is —C(O)— and R² is heteroaryl.
 27. Thecompound of claim 1, wherein X is —C(O)— and R² is carbocyclyl.
 28. Thecompound of claim 27, wherein R² is C₃-C₇ carbocyclyl.
 29. The compoundof claim 1, wherein X is —C(O)— and R² is heterocyclyl.
 30. The compoundof claim 1, wherein X is —C(O)—NH— and R² is aryl.
 31. The compound ofclaim 1, wherein X is —C(O)—NH— and R² is heteroaryl.
 32. The compoundof claim 1, wherein X is —C(O)—NH— and R² is carbocyclyl.
 33. Thecompound of claim 32, wherein R² is C₃-C₇ carbocyclyl.
 34. The compoundof claim 1, wherein X is —C(O)—NH— and R² is heterocyclyl.
 35. Thecompound of claim 1, wherein X is —NH— and R² is aryl.
 36. The compoundof claim 1, wherein X is —NH— and R² is heteroaryl.
 37. The compound ofclaim 1, wherein X is —NH— and R² is carbocyclyl.
 38. The compound ofclaim 37, wherein R² is C₃-C₇ carbocyclyl.
 39. The compound of claim 1,wherein X is —NH— and R² is heterocyclyl.
 40. The compound of claim 1,wherein X is —NH—C(O)— and R² is aryl.
 41. The compound of claim 1,wherein X is —NH—C(O)— and R² is heteroaryl.
 42. The compound of claim1, wherein X is —NH—C(O)— and R² is carbocyclyl.
 43. The compound ofclaim 42, wherein R² is C₃-C₇ carbocyclyl.
 44. The compound of claim 1,wherein X is —NH—C(O)— and R² is heterocyclyl.
 45. The compound of claim1, wherein X is —O— and R² is aryl.
 46. The compound of claim 1, whereinX is —O— and R² is heteroaryl.
 47. The compound of claim 1, wherein X is—O— and R² is carbocyclyl.
 48. The compound of claim 47, wherein R² isC₃-C₇ carbocyclyl.
 49. The compound of claim 1, wherein X is —O— and R²is heterocyclyl.
 50. The compound of claim 1, wherein X is —S— and R² isaryl.
 51. The compound of claim 1, wherein X is —S— and R² isheteroaryl.
 52. The compound of claim 1, wherein X is —S— and R² iscarbocyclyl.
 53. The compound of claim 52, wherein R² is C₃-C₇carbocyclyl.
 54. The compound of claim 1, wherein X is —S— and R² isheterocyclyl.
 55. The compound of claim 1, wherein X is —SO₂— and R² isaryl.
 56. The compound of claim 1, wherein X is —SO₂— and R² isheteroaryl.
 57. The compound of claim 1, wherein X is —SO₂— and R² iscarbocyclyl.
 58. The compound of claim 57, wherein R² is C₃-C₇carbocyclyl.
 59. The compound of claim 1, wherein X is —SO₂— and R^(e)is heterocyclyl.
 60. The compound of claim 1, wherein G is X¹-alkyl. 61.The compound of claim 60, wherein X¹ is a bond.
 62. The compound ofclaim 61, wherein the alkyl is a C₁-C₄ alkyl.
 63. The compound of claim62, wherein the alkyl is a 1-hydroxyalkyl.
 64. The compound of claim 61,wherein the alkyl is a C₂-C₄ 1-hydroxyalkyl.
 65. The compound of claim60, wherein X¹ is —C(O)—.
 66. The compound of claim 65, wherein thealkyl is a C₁-C₄ alkyl.
 67. The compound of claim 60, wherein X¹ is—C(O)—NH—.
 68. The compound of claim 67, wherein the alkyl is a C₁-C₄alkyl.
 69. The compound of claim 60, wherein X¹ is —NH—.
 70. Thecompound of claim 69, wherein the alkyl is a C₁-C₄ alkyl.
 71. Thecompound of claim 60, wherein X¹ is —NH—C(O)—.
 72. The compound of claim71, wherein the alkyl is a C₁-C₄ alkyl.
 73. The compound of claim 60,wherein X¹ is —O—.
 74. The compound of claim 73, wherein the alkyl is aC₁-C₄ alkyl.
 75. The compound of claim 60, wherein X¹ is —S—.
 76. Thecompound of claim 75, wherein the alkyl is a C₁-C₄ alkyl.
 77. Thecompound of claim 60, wherein X¹ is —SO₂—.
 78. The compound of claim 77,wherein the alkyl is a C₁-C₄ alkyl.
 79. The compound of claim 1, whereinX is alkylene-O—.
 80. The compound of claim 1, wherein X is alkylene-O—,and R² is aryl.
 81. The compound of claim 1, wherein X is alkylene-O—,and R² is heteroaryl.
 82. The compound of claim 1, wherein X isalkylene-O—, and R² is carbocyclyl.
 83. The compound of claim 82,wherein R² is C₃-C₇ carbocyclyl.
 84. The compound of claim 1, wherein Xis alkylene-O—, and R² is heterocyclyl.
 85. The compound of claim 79,wherein the alkylene is a C₁-C₃ alkylene.
 86. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of claim 1 or a pharmaceutically acceptable salt thereof.
 87. Amethod for inhibiting histone demethylase-dependent cellularproliferation comprising contacting a cell with the compound of claim 1or a pharmaceutically acceptable salt thereof.
 88. A method forinhibiting a histone demethylase enzyme comprising contacting thehistone demethylase enzyme with the compound of claim 1 or apharmaceutically acceptable salt thereof.
 89. A method for treatingbreast cancer comprising administering to a patient in need thereof aneffective amount of a pharmaceutical composition as described in claim86.